Many Faces of TRIM Proteins on the Road from Pluripotency to Neurogenesis

Abstract

Tripartite motif (TRIM) proteins participate in numerous biological processes. They are the key players in immune system and are involved in the oncogenesis. Moreover, TRIMs are the highly conserved regulators of developmental pathways in both vertebrates and invertebrates. In particular, numerous data point to the participation of TRIMs in the determination of stem cell fate, as well as in the neurogenesis. TRIMs apply various mechanisms to perform their functions. Their common feature is the ability to ubiquitinate proteins mediated by the Really Interesting New Gene (RING) domain. Different C-terminal domains of TRIMs are involved in DNA and RNA binding, protein/protein interactions, and chromatin-mediated transcriptional regulation. Mutations and alterations of TRIM expression cause significant disturbances in the stem cells' self-renewal and neurogenesis, which result in the various pathologies of the nervous system (neurodegeneration, neuroinflammation, and malignant transformation). This review discusses the diverse molecular mechanisms of participation of TRIMs in stem cell maintenance and self-renewal as well as in neural differentiation processes and neuropathology.

Introduction

Tripartite motif (TRIM) proteins usually contain three common motifs at the N-terminus: the Really Interesting New Gene (RING) domain, one or two B-box domains, and the coiled-coil (CC) domain [1,2] (Fig. 1). The RING domain is composed of 40–60 amino acids and is responsible for E3 ubiquitin ligase activity, which can mediate protein conjugation either with the ubiquitin [2], or with the small ubiquitin-like molecule modifier (SUMO) [3], or with the neural precursor cell (NPC)-expressed developmentally downregulated 8 (NEDD8) ubiquitin-like protein [4]. The B-boxes promote TRIM self-association, as well as interactions with other proteins [2]. The CC domain is a hyperhelical structure, which is responsible for dimerization of TRIM proteins and higher-order TRIM oligomerization [2].

FIG. 1.

Schematic representation of the TRIM family protein domain structure. RING domain; B1, B-box 1; B2, B-box 2; CC, coiled-coil region. The most frequent C-terminal domains are also shown on the right side of the scheme. RING, Really Interesting New Gene; TRIM, tripartite motif.

The C-terminal part of TRIMs contains various domains, which are not conserved between all members of the TRIM family. For example, the PRYSPRY domain promotes protein/protein interactions [5]. The C-terminal subgroup one signature (COS) motif interacts with microtubules [6]. The fibronectin type III motif (FN3) contains b-sandwich structure and is detected in cell surface proteins, all of which are involved in a molecular recognition function [7]. The Plant Homeodomain (PHD)-Bromo domain is associated with chromatin-based transcriptional regulation [8].

The ADP-ribosylation factor-like (ARF) domain mediates GTP hydrolysis activity [9]. The NHL domain is involved in protein and RNA binding, while the filamin domain possessing an immunoglobulin-like structure takes part in messenger RNA (mRNA) regulation in TRIM-NHL proteins [10]. Finally, the meprin and tumor-necrosis factor receptor-associated factor homology (MATH) domain takes part in receptor binding and oligomerization [11] (Fig. 1). Depending on the presence of different C-terminal domains, TRIM proteins are divided into 11 groups [12].

The majority of TRIMs possess the ubiquitin ligase activity due to their RING domain, which is critical for many cellular functions, including the signal transduction and regulation of innate immunity [13]. Although TRIM family is characterized by TRIM, some TRIM-like members lack one or more of these domains (eg, the RING domain is missed in TRIM14 [14] and in TRIM16 [15]), but possess the corresponding C-terminal domains and can be assigned to one of the 11 TRIM groups [12].

Over the last few years, increasing evidence has suggested that members of the TRIM family play an important role in the stem cell differentiation and pluripotency, apoptosis and autophagy, regulation of transcription and cell cycle progression, signaling pathways, chromatin remodeling, as well as neurogenesis, and oncogenesis [16,17]. However, the particular interest to those proteins has been attracted due to their involvement in innate immune system [16,18 –20]. More than 70% of TRIMs are directly implicated in the innate and intrinsic immune response [21]. The antiviral strategies employed by TRIMs are divided into three broad categories: the modulation of innate immune sensing or signaling, direct restriction of viruses, and regulation of autophagy-mediated antiviral defense. In recent years, an increasing number of studies have indicated that many antiviral signaling pathways are TRIM regulated [20,22].

At the same time, TRIMs are also involved in many other key cellular processes. In particular, they play an essential role in stem cell functioning and differentiation, as well as in neurogenesis (Fig. 2). The latter topics that until now were paid less attention will be considered in the current review.

FIG. 2.

The established functions of TRIM family members.

Functions of TRIMs in Stem Cells

The participation of TRIMs in stem cell regulation just begins to attract the attention of researchers. Currently, at least 10 TRIMs are known to be involved in the maintenance of stem cells' pluripotency and in regulation of their differentiation (Table 1). Proteins belonging to the C-VI (TRIM24, TRIM28, and TRIM33, containing PHD-Bromo domain), C-VII (TRIM-NHL proteins: TRIM32 and TRIM71), and to the most representative C-IV (TRIM6, TRIM14, TRIM25, and TRIM26, containing a PRYSPRY domain) subfamilies [12] are actively involved in stem cell regulation.

Table 1.

Tripartite Motif Proteins in Stem Cells

TRIM proteins	Effects in stem cells
TRIM6	Maintains pluripotency of the ESCs upstream of NANOG [23].
TRIM8	Binds HSP90β, which interacts with STAT3 and selectively downregulates transcription of Nanog in mESCs and leads to consequent differentiation [31].
TRIM14	Increases the formation of embryoid bodies from mESCs [24]. Overexpression increases mesodermal differentiation and decreases ectodermal differentiation of mESCs [25].
TRIM24	Ubiquitinates P53 in ESC and prevents apoptosis [38] and differentiation [33]. Interacts with multiple enhancers of OCT4, SOX2, and NANOG thus maintaining the pluripotency of mESCs [32].
TRIM25	Highly expressed in mESCs compared with differentiated cells [26]. Participates in resolving replication stress in mESCs [29].
TRIM26	Promotes ubiquitination and degradation of PHF20 and prevents the activation of Oct4 expression thus leading to not fully reprogrammed iPSCs [30].
TRIM28	In stem cells, interacts with the KRAB-ZNF protein and recruits histone-modifying complexes (NuRD, SETDB1, and HP1) to the specific DNA motifs. TRIM28/KRAB-ZNF complexes promote the epigenetic silencing of gene [34]. During somatic cell reprogramming into iPSCs, interacts with three KRAB-ZNF factors (ZNF114, ZNF483, and ZNF589) and maintains pluripotent state [35,43]. H3K9me3-mediated silencing of exogenous proviruses and ERVs [40] as well as human-specific endogenous retroelements [41] in ESCs. Phosphorylated TRIM28 forms complex with transcription factor Oct4 and induces transcription of ES cell-specific genes thereby maintaining the undifferentiated state of stem cells [35]. Knockdown of TRIM28 enhances reprogramming of somatic cells [44].
TRIM32	Inhibits somatic cell reprogramming of mouse embryonic fibroblasts into iPSCs, directly regulates two of the four Yamanaka Factors (c-MYC and OCT4) [54].
TRIM33	TRIM33-SMAD2/3 binds to the promoters of mesendoderm regulators and triggers stem cell differentiation of mESC [37]. Regulates Wnt-mediated response of Mixl1 during mesendoderm differentiation in mESCs [45]. Required for the normal maturation of embryoid bodies in mESCs [46].
TRIM71	Highly expressed in mESCs compared with differentiated cells [26]. Associates with Argonaute 2 and miRNAs, represses expression of CDKN1A and facilitates the G1-S transition to promote rapid mESC self-renewal [47]. Promotes reprogramming of differentiated cells into iPSCs by overcoming the let-7 barrier to reprogramming [53]. Stabilizes SHCBP1 and promotes FGF/ERK signaling, which controls self-renewal and differentiation in ESCs [49].

CDKN1A, Cyclin-Dependent Kinase Inhibitor 1A; ERK, extracellular signal-regulated kinase; ERVs, endogenous retroviruses; ESC, embryonic stem cell; FGF, Fibroblast growth factor; HP1, heterochromatin protein 1; HSP, heat shock protein; iPSC, induced pluripotent stem cell; KRAB-ZNF, Krüppel-associated box domain zinc finger; mESC, mouse embryonic stem cell; miRNA, microRNA; PHF, PHD Finger Protein; SETDB1, SET domain bifurcated 1; SHCBP1, SHC SH2 domain-binding protein 1; STAT, Signal Transducer and Activator of Transcription; TRIM, tripartite motif.

TRIM proteins, carrying PRYSPRY domain (C-IV subfamily)

C-IV subfamily consists of thirty-eight members, most of which are implicated in the antiviral response. At the same time, some data demonstrate the active involvement of several TRIMs of this subfamily in the maintenance of pluripotency and stem cells' self-renewal. The RING domain, common to most TRIM proteins, also takes part in the realization of these functions. For example, in mouse embryonic stem cells (mESCs), TRIM6 ubiquitinates c-MYC and weakens its transcriptional activity. However, overexpression of TRIM6 leads to increase of the expression of NANOG, the marker of the pluripotency of ESCs. Knockdown of TRIM6 induces differentiation of ESCs, suggesting that TRIM6 participates in maintenance of the pluripotency upstream of NANOG [23] (Table 1).

Another member of the C-IV subfamily, TRIM14, lacks the RING domain, but is able to promote the differentiation of mESCs into the embryoid bodies [24]. In addition, TRIM14 overexpression in mESCs does not influence endodermal, but increases mesodermal, and decreases ectodermal differentiation in these cells [25].

Analyses of mESCs have revealed several RNA-binding proteins, which are expressed significantly stronger in ESCs as compared with differentiated cells, implying their role in the maintenance of stem cells. Among them are TRIM25 and TRIM71 [26]. Nevertheless, unlike in TRIM71, where NHL domain supports RNA-binding, in TRIM25 the PRYSPRY domain is responsible for binding to RNA [27]. TRIM25 takes part in the degradation of precursor of let-7 microRNA (miRNA), the regulator of cell differentiation, as the RNA-specific cofactor for Lin28s/TuT4-mediated uridylation [28].

In 2018, Zhao et al. [29] described a new mechanism of resolving replication stress in mESCs. The mESC-specific Filia-Floped complex overcomes stalled replication forks by recruiting TRIM25. Next, TRIM25 binds and ubiquitinates the Bloom syndrome helicase (BLM), a key regulator of stalled replication forks. In this way, TRIM25 ensures genomic stability of mESCs [29]. Another member of this subfamily, TRIM26, is required to generate induced pluripotent stem cells (iPSCs) during somatic cell reprogramming. This protein ubiquitinates by its RING domain the PHD Finger Protein (PHF)20, promoting degradation of PHF20, and prevents the activation of Oct4 expression thus leading to not fully reprogrammed iPSCs [30].

C-V subfamily of TRIM proteins

The C-V subfamily of TRIMs does not contain the known domains at the C-terminus. TRIM8 is the only member of C-V subfamily that was found to participate in stem cell maintenance (Table 1). TRIM8 is detected in undifferentiated mESCs, whereas differentiated cells do not express this protein [31]. Okumura et al. [31] demonstrated that TRIM8 binds to heat shock protein (HSP) 90β, which, in turn, regulates the translocation of phosphorylated Signal Transducer and Activator of Transcription (STAT)3 into the nucleus. These processes lead to the downregulation of transcription of NANOG in ESCs. Interestingly, RING domain is not involved in these functions of TRIM8 [31].

TRIM proteins, containing PHD-Bromo domain (C-VI subfamily)

TRIM24, TRIM28, and TRIM33 participate in the regulation of the balance between maintenance of pluripotency and differentiation of the stem cells [32 –37]. It was shown that PHD and Bromodomain of TRIM24 jointly recognize both the unmethylated lysine 4 and acetylated lysine 23 or 18 of histone H3 [8]. TRIM24 binds to multiple enhancers of genes encoding OCT4, SOX2, and NANOG (the transcription factors essential to maintain the pluripotent embryonic stem cell phenotype), activates them and thus maintains the pluripotency of mESCs. At the same time, TRIM24 decreases the expression of developmental genes, but activates the cell cycle genes in mESCs [32].

In addition, TRIM24 binds to P53, ubiqutinates it by the RING domain, which promotes P53 degradation and thus prevents spontaneous ESCs apoptosis [38], as well as differentiation [33]. It was shown that TRIM24 and HDM2 [also known as Mouse Double-Minute 2 Homolog (MDM2)], both possessing E3 ubiquitin ligase activity, are the negative regulators of P53 in human ESCs (hESCs). They promote P53 degradation, thereby preventing differentiation. In hESCs, P53 is deacetylated and maintained at the low level in the nucleus. Being acetylated at lysine 373, P53 is released from the HDM2 and TRIM24 and interacts with Cyclin-Dependent Kinase Inhibitor 1A (CDKN1A; P21), thereby promoting the G1 phase of cell cycle and preventing cell death. Additionally, P53 can stimulate expression of miR-34a and miR-145, which suppresses the expression of major stem cell factors OCT4, Kruppel-Like Factor 4 (KLF4), Lin-28 Homolog A (LIN28A), and SOX2 in hESCs, thus preventing their self-renewal [33].

PHD domain of TRIM28, another member of the C-VI subfamily, was shown to direct SUMO conjugation with its own bromodomain, and this sumoylation is necessary for the Kruppel-associated box domain zinc finger (KRAB-ZNF) protein TRIM28-mediated transcriptional repression [39]. TRIM28 interacts with the KRAB-ZNF protein and recruits various histone-modifying complexes [NuRD complex, SET domain bifurcated 1 (SETDB1)—H3K9-specific histone methyltransferase, and heterochromatin protein 1 (HP1)—the H3K9me2/3 reader] to the specific histone marks. As a result, TRIM28/KRAB-ZNF promotes transcription silencing of genes [34].

TRIM28, along with zinc finger protein ZFP809 and SETDB1 (ESET) factors, is responsible for H3K9me3-mediated silencing of exogenous proviruses and endogenous retroviruses (ERVs) in ESCs [40]. TRIM28 was also shown to silence human-specific endogenous retroelements in hESCs [41]. The phosphorylated TRIM28 variant forms complex with the transcription factor Oct4 and induces expression of ESC-specific genes thereby maintaining their undifferentiated state [35].

TRIM28 plays a crucial role in somatic cell reprogramming into the iPSCs [36,42,43]. Oleksiewicz et al. [36] have demonstrated that upon reprogramming into iPSCs, the interaction of three KRAB-ZNF factors (ZNF114, ZNF483, and ZNF589) with TRIM28 is necessary for the maintenance of the pluripotent state and for DNA methylation of the major differentiation genes. Klimczak et al. [43] have received similar data. At the same time, Miles et al. [44] have shown that TRIM28 represses the transcription of ERVs and the genes located in the surrounding genome regions in somatic cells. These regions are enriched in the H3K9me3 marks, and knockdown of TRIM28 leads to more decondensed chromatin state promoting reprogramming of somatic cells. Thus, TRIM28 may be a key regulator of gene expression in the repressive chromatin regions upon reprogramming.

Another member of the subfamily, TRIM33 is able to form complex with Mothers against decapentaplegic homolog (Smad)2/3 through its PHD and Bromo domains, which mediates the signal transduction from the receptors of transforming growth factor beta (TGFβ) superfamily. The complex replaces HP1γ at the promoters of mesendoderm regulators Gsc and Mixl1 marked by H3K9me3 in stem cells. Binding of TRIM33-Smad2/3 complex makes these promoters available for the Smad4-Smad2/3 complex, which recruits histone acetyltransferases, switches the master regulators Gsc and Mixl1 from poised to activated state, and thereby promotes subsequent mesendoderm differentiation of mESCs [37]. Xia et al. [45] have shown that TRIM33 can regulate Wnt-mediated response of Mixl1 in mESCs. Besides, TRIM33 is necessary for the normal maturation of embryoid bodies in mESCs [46].

TRIM-NHL proteins (C-VII subfamily)

TRIM71 is an important regulator of the pluripotency in mESCs [26]. One of the known functions of NHL domain is RNA binding. TRIM71 maintains stem cell identity, contributes to the G1-S transition and promotes ESCs self-renewal. To perform these functions, it binds to Argonaute2 and microRNAs and inhibits the expression of CDKN1A [47]. However, Mitschka et al. [48] have shown that the loss of TRIM71 in mESCs does not affect the expression of such regulators of pluripotency as NANOG and OCT4. Recently, it was shown that TRIM71 stabilizes SHC SH2 domain-binding protein 1 (SHCBP1) and promotes fibroblast growth factors (FGF)/extracellular signal-regulated kinase (ERK) signaling, which controls self-renewal and differentiation in ESCs. The authors described new long noncoding RNA Trincr1 (TRIM71 interacting noncoding RNA1) that represses TRIM71 and its ability to stabilize SHCBP1 [49].

Besides, TRIM71 can ubiquitinate P53 and counteract P53-dependent apoptotic and differentiation signaling pathways in TRIM71-inducible mESCs [50]. TRIM71 is negatively regulated by let-7 miRNA, which is the inhibitor of stem cells' self-renewal [51,52]. let-7 inhibition and subsequent activation of TRIM71 promotes reprogramming of differentiated cells into iPSCs [53]. Unlike TRIM71, TRIM32 does not maintain stem cell pluripotency. It inhibits reprogramming of mouse embryonic fibroblasts into iPSCs, through ubiquitination by RING domain and subsequent proteasomal degradation of c-MYC and OCT4 [54]. These data demonstrate that, despite the structural similarity, TRIMs can either favor or prevent stem cell differentiation (Table 1).

Thus, TRIMs play the key role in various processes in stem cells (Table 1). Their functions may be linked to either the ability to ubiquitinate proteins leading to their degradation, or to the different functionalities mediated by various C-terminal domains. Interestingly, some properties of TRIMs, such as RNA binding, can be performed by distinct C-terminal domains (NHL or PRYSPRY). In conclusion, this combination of various domains is responsible for a wide variety of properties of TRIM proteins in stem cells.

Functions of TRIM Proteins in Embryogenesis

As could be expected, besides involvement in the stem cells' regulation, TRIMs actively participate in the early stages of embryogenesis [55 –64] (Table 2). For example, in Xenopus laevis oocytes and unfertilized eggs, Trim36 (subfamily C-I) ubiquitination activity is necessary for microtubule assembly. It attenuates the dynamics of plus-end microtubule growth and controls its orientation [55,56]. At the same time, TRIM28 (subfamily C-VI) was shown to participate in embryonic epigenetic reprogramming. The absence of maternal TRIM28 leads to the hypomethylation of Rbmy1a1 gene promoter. Its activation causes developmental arrest and male-specific early embryonic lethality [57].

Table 2.

Tripartite Motif proteins in Embryogenesis

TRIM proteins	Effects in embryogenesis
TRIM11	Ubiquitinates PAX6 and promotes PAX6 degradation, thereby inhibiting PAX6 transcriptional activity [64].
TRIM28	Participates in embryonic epigenetic reprogramming. Absence of maternal TRIM28 leads to activation of Rbmy1a1 gene that causes developmental arrest and male-specific early embryonic lethality [57].
TRIM33 (TIF1γ)	Forms the complex with Smad4, ubiqutinates it and thereby negatively regulates Nodal/TGFβ signaling. In the trophoblast, modulates Nodal activity to balance stem cell self-renewal and differentiation. In epiblast, regulates Smad4 for the correct formation of anterior primitive streak derivatives [58].
TRIM36	In Xenopus laevis oocytes and unfertilized eggs, Trim36 attenuates the dynamics of plus-end microtubule growth and controls its orientation [55,56]. Knockdown of Trim36 inhibits somite formation from mesodermal tissue during early embryogenesis of X. laevis [62].
TRIM59	A critical regulator of early embryo development from the blastocyst stage to gastrula through Trim59-mediated polymerization of F-actin [59]. Depletion of TRIM59 downregulates the expression of primary germ layer formation-associated genes (Brachyury, lefty2, Cer1, Otx2, Wnt3, and Bmp4), disrupts the formation of primary germ layers and leads to the embryonic lethality [59].
TRIM69	Expressed in zebrafish embryos brain at different stages of early development [63].
TRIM71	TRIM71 mutants manifest the embryonic lethality [60,61].

PAX, Paired Box; TGFβ, transforming growth factor beta.

Another TRIM protein from subfamily C-VI, TRIM33, is required for the restriction of Nodal Growth Differentiation Factor (Nodal)/TGFβ signaling during early vertebrate embryogenesis. TRIM33 forms the complex with Smad4, which participates in the intracellular signal transduction in response to the Nodal signaling, ubiqutinates it, and thereby can negatively regulate Nodal/TGFβ signaling. In the trophoblast, TRIM33 modulates Nodal activity to balance stem cells' self-renewal and differentiation. In epiblast, TRIM33-mediated regulation of Smad4 is responsible for the correct formation of anterior primitive streak derivatives [58].

TRIM59 (subfamily C-XI) is shown to be important in early embryo development (from the blastocyst stage to the gastrula) [59]. Depletion of TRIM59 downregulates the expression of primary germ layer formation-associated genes (Brachyury, lefty2, Cer1, Otx2, Wnt3, and Bmp4), disrupts the formation of primary germ layers, and leads to the embryonic lethality. TRIM59 also ubiquitinates F-actin and promotes its polymerization during gastrulation [59]. At the same time, TRIM71 mutants (truncated protein without NHL domain and 3’UTR, the site of the let-7 miRNA binding) manifest the embryonic lethality, thus indicating the important role of the TRIM71 in embryogenesis [60,61].

Yoshigai et al. [62] detected Trim36 (subfamily C-I) expression during early embryogenesis of X. laevis, mainly in the nervous system and in a section of the posterior somite. Knockdown of Trim36 inhibits somite formation from mesodermal tissue [62]. The expression of the protein of C-IV group, trim69 (the homologous gene of human TRIM69), was revealed in zebrafish embryo brain at different stages of early development [63]. TRIM11 (subfamily C-IV) ubiquitinates Paired Box (PAX)6, which is an important developmental regulator, and promotes its degradation, thereby inhibiting PAX6 transcriptional activity [64].

Thus, the TRIMs can participate in the embryogenesis from the very beginning. At later stages, they are involved in the processes of maturation of the nervous system.

TRIM-Mediated Regulation of the Nervous System Development and Functioning

Most TRIMs, linked to the stem cells' regulation, are reported to be also involved in the development and functioning of the nervous system (Table 3). Several TRIMs affect the early stages of neurogenesis, as well as the development of the nervous system. Below, we will focus on the existing data concerning the functions of TRIMs in the normal and pathological processes in the nervous system.

Table 3.

Tripartite Motif Proteins Associated with Neurogenesis

TRIM proteins	Effects upon neurogenesis
TRIM2	Regulates neuronal polarization and axon outgrowth during development [86]. Ubiquitinates the neurofilament light chain, mediates its degradation, and thereby prevents axonopathy [87]. Ubiquitinates and promotes the degradation of Bim in neurons following brief ischemia and thus protects them [88].
TRIM3	Regulates NSC proliferation and differentiation by influencing on the Notch signaling pathway [89]. Increases the degradation of GKAP by ubiquitination, thereby inhibiting growth of dendritic spine heads in rat hippocampal neurons [90]. Polyubiquitinates γ-actin and regulates the timing of hippocampal plasticity, learning, and memory [94]. Regulates the cell surface expression of GABA(A) receptors and thereby can mediate seizure susceptibility [95].
TRIM8	In embryonic NSCs, causes the enrichment of pathways related to the neurotransmission and to the CNS functions [77]. Knockdown promotes glial differentiation [78]. Activates STAT3 signaling by suppressing the expression of PIAS3 and maintains stemness and self-renewing capabilities of glioblastoma stem-like cells [78].
TRIM9	During mouse embryogenesis (from E13.5) expressed mainly in the CNS, in particular in developing neocortex, dorsal thalamus, midbrain, basal area of the hindbrain and in the spinal cord [65]. In the adult brain, is detected in the Purkinje cells of the cerebellum, in the hippocampus, and in the cortex [65]. Ubiquitinates netrin-1 receptor DCC and thereby decreases dendritic and axonal branching of adult-born hippocampal neurons as well as cortical neurons [66 –68]. Influences on hippocampal-dependent spatial learning and memory in the Morris Water Maze [66]. Ubiquitinates polymerase VASP and modulates the filopodia density and stability in response to netrin in cortical neurons [69]. Interacts with SNAP25 and thereby inhibits SNARE complex formation upon exocytosis in axon branching [67].
TRIM11	Inhibits PAX6-dependent corticogenesis [64]. Specifies noradrenergic neurons in CNS and PNS by direct interaction with PHOX2B [74].
TRIM16	Participates in the differentiation of ganglia cells. Affects cell cycle progression through Cyclin D1 and p27 [15].
TRIM17	Controls neuronal apoptosis in cerebellar granule neurons through ubiquitination and subsequent degradation of MCL-1 [75]. Binds preferentially to SUMOylated forms of NFATc3, inhibits NFATc3 nuclear translocation and activity in neuronal apoptosis [76].
TRIM28	TRIM28-mediated histone modifications in NPCs repress the ERVs [80 –82]. Controls olfactory bulb neurogenesis in complex with long noncoding RNA Paupar and Pax6 [84]. Knockout of TRIM28 in mice leads to changes in exploratory activity, spatial learning, and memory [85].
TRIM32	Determines cell fate in NSCs and affects the equilibrium between stem cell maintenance and neuronal differentiation, controls the production of olfactory bulb neurons in adults [93 –96]. Loss of TRIM32 changes the behavior in the open field test, but does not influence exploratory and anxiety-related behavior as well as spatial learning [97]. Promotes the degradation of c-MYC by ubiquitination, enhances neuronal differentiation, and suppresses self-renewal [95]. Binds the RNA helicase DDX6, Ago2, and RNA-binding protein Pum1 in vivo. This complex supposedly is involved in let-7a miRNA activation during NSC differentiation 93]. Promotes stability of retinoic acid receptor α, resulting in the enhancement of neural differentiation [94].
TRIM33	In complex with SMAD4, controls proliferation, differentiation, and cell cycle exit of NSCs in midbrain in cortical NSCs [83].
TRIM44	Expressed in neuroblasts and developing neurons in the adult brain of mouse and in embryo brain from day 14 [79].
TRIM46	Controls microtubule organization during axon formation [70].
TRIM67	Promotes neural differentiation including neuritogenesis and negatively regulates RAS signaling through ubiquitination and degradation of 80K-H [71]. Required for appropriate brain development and cognitive ability and social behavior of mice [72].
TRIM69	Interacts with c-JUN and subsequent negatively regulates its expression. Its knockdown causes significant defects in embryo brain and attenuates neuronal differentiation markers [63].
TRIM71	The loss of TRIM71 in Trim71(−/−) mESCs promotes the expression of neural markers and upregulation of several miRNA (let-7e, mir-132, mir24–2, mir-200) and directs mESCs toward neural differentiation [48]. In adults, expressed in the ependymal cells lining the walls of the four ventricles [60]. Negatively regulated by let-7 miRNA. This leads to the correct anterior neural tube closure during embryogenesis [60,61].

Bim, Bcl-2-interacting mediator of cell death; CNS, central nervous system; MCL, Myeloid Cell Leukemia; NFATc, Nuclear Factor of Activated T Cells; NPC, neural precursor cell; NSC, neural stem cell; PHOX, Paired Mesoderm Homeobox Protein; PIAS3, protein inhibitor of activated STAT3; PNS, peripheral nervous system; Pum1, Pumilio 1; SNAP25, Synaptosome-Associated Protein 25; SUMO, small ubiquitin-like molecule modifier; VASP, Vasodilator-Stimulated Phosphoprotein.

C-I subfamily TRIM proteins

The C-I TRIMs possess several C-domains, including a COS-box motif, a FN3 domain, and the PRYSPRY domain. Brain-specific E3 ubiquitin ligase TRIM9 actively takes part in the functioning of mouse central nervous system (CNS). During mouse embryogenesis (from E13.5), it is expressed mainly in the CNS, in particular in developing neocortex, dorsal thalamus, midbrain, basal area of the hindbrain, and in the spinal cord [65]. In adult brain, this protein is mainly found in Purkinje cells of the cerebellum, as well as in the pyramidal cells of the hippocampus, and in the external layers of the cortex [65]. Moreover, TRIM9 interacts and ubiquitinates netrin-1 receptor DCC and thereby decreases dendritic and axonal branching of adult-born hippocampal neurons as well as cortical neurons [66 –68].

The Trim9 deletion in mice causes the impairment of hippocampal-dependent spatial learning and memory in the Morris Water Maze [66]. Besides, Menon et al. [69] have shown that TRIM9 localizes to neuronal growth cone filopodia, binds to and ubiquitinates polymerase vasodilator-stimulated phosphoprotein (VASP), and modulates the filopodia density and stability in response to netrin in cortical neurons [69]. Moreover, TRIM9 directly interacts with Synaptosome-Associated Protein 25 (SNAP25), and thereby inhibits N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex formation located on the plasma membrane, which plays a key role in exocytosis in axon branching [67]. Abundant axonal arborization and unwanted innervation may cause neurodevelopmental disorders. Therefore, TRIM9 is an important regulator of the correct axon branching.

Another member of this subfamily, TRIM46, controls the initial polarization of neuronal cells and microtubule organization during axon formation. These properties are mediated by the C-terminal COS domain, which is responsible for interaction with microtubules [70]. Mouse TRIM67 inhibits cell proliferation and induces neural differentiation, including neuritogenesis. This protein interacts with Brain-Specific Phosphatidic Acid Phosphatase-Like Protein 1 (PRG-1) and Protein Kinase C Substrate 80K-H, ubiquitinates and promotes further degradation of 80K-H, and negatively regulates RAS signaling in the neuroblastoma cell line N1E-115 followed by growth arrest and neuritogenesis in NPCs [71]. Besides, Boyer et al. [72] have shown that TRIM67 is essential for the correct morphology of several brain regions as well as for cognitive abilities and social behavior of mice [72,73].

C-IV subfamily TRIM proteins

TRIM11, through its C-terminal SPRY domain, directly interacts with the homeodomain-containing transcription factor, Paired Mesoderm Homeobox Protein (PHOX) 2B, which plays an essential role during the development of noradrenergic neurons in both the CNS and the peripheral nervous system [74]. TRIM11 inhibits PAX6-dependent corticogenesis. Depletion of endogenous TRIM11 in the mouse cortex leads to an accumulation of inclusion bodies, containing PAX6, and to apoptosis [64]. TRIM16 participates in the differentiation of ganglia cells. It affects cell cycle progression through Cyclin D1 and p27. Known domains do not take part in these functions suggesting the presence of other important functional sites [15].

TRIM17 promotes neuronal apoptosis through ubiquitination and subsequent degradation of phosphorylated form of BCL2-like antiapoptotic protein Myeloid Cell Leukemia (MCL)-1 [75]. In addition, TRIM17 interacts with the SUMOylated form of Nuclear Factor of Activated T Cells (NFATc)3, which is a proapoptotic factor of cerebellar granule neurons. This SUMOylation prevents nuclear localization of NFATc3 [76]. The knockdown of trim69 in zebrafish causes significant defects in embryo brain and attenuates neuronal differentiation markers. TRIM69 mediates these effects through interaction with c-JUN and subsequent negative regulation of its expression [63].

C-V subfamily TRIM proteins

TRIM8 and TRIM44, belonging to the C-V subfamily of TRIMs, were also shown to participate in early neurogenesis. RNA-seq analysis of TRIM8-expressing primary mouse embryonic neural stem cells (NSCs) [77] resulted in the identification of CNS-related pathways that were especially enriched in comparison to the control cells. TRIM8 interacts with STAT3 and increases its transcriptional activity by direct binding with the STAT3-inducible element (SIE) sequences [77]. In addition, TRIM8 can ubiquitinate and promote proteasomal degradation of protein inhibitor of activated STAT3 (PIAS3) and thereby activates STAT3. The overexpression of TRIM8 increases the expression of p-STAT3, c-MYC, SOX2, NESTIN, and CD133 (Prominin 1) and enhances glioma stem cell self-renewal [78]. TRIM44 is expressed in neuroblasts and in developing neurons in adult mice brain and in embryonic brain from day 14 [79].

C-VI subfamily TRIM proteins

TRIM28 and TRIM33 belonging to C-VI subfamily and playing the key role in self-renewal or differentiation of the pluripotent stem cells were also shown to regulate NSCs proliferation or differentiation [80 –83]. TRIM28 represses ERVs and the nearby protein-coding genes by maintaining a localized heterochromatin regions in NPCs in the same manner as in pluripotent stem cells [80 –82]. Recently, Pavlaki et al. [84] have demonstrated that TRIM28 itself is regulated by long noncoding RNA Paupar, which forms a ribonucleoprotein complex with TRIM28 and transcription factor PAX6 on chromatin region enriched for regulators of neural proliferation and differentiation. This complex is important for controlling of olfactory bulb neurogenesis. Interestingly, knockout of TRIM28 in mice leads to changes in exploratory activity, spatial learning, and memory suggesting a role of TRIM28 in the hippocampus [85].

Another protein of this subfamily, TRIM33, in complex with SMAD4, regulates the TGFβ pathway and thereby controls proliferation, differentiation, and cell cycle exit of NSCs in the midbrain [83].

C-VII subfamily TRIM proteins

The C-VII subfamily of TRIM-NHL proteins participates in neurogenesis, employing their E3 ubiquitin ligase activity or functions of NHL domain (Table 2). TRIM2 promotes specification of axons in cultured mouse hippocampal neurons [86]. It ubiquitinates the neurofilament light chain, mediates its degradation, and thereby prevents axonopathy [87]. TRIM2 also ubiquitinates and promotes the degradation of proapoptotic factor Bcl-2-interacting mediator of cell death (Bim) in neurons following brief ischemia and thus contributes to rapid ischemic tolerance neuroprotection [88].

TRIM3 regulates NSC proliferation and differentiation by influencing on the Notch signaling pathway [89]. TRIM3 increases the degradation of postsynaptic density proteins, Discs Large Homolog-Associated Protein 1 (DLGAP1/GKAP/SAPAP) by ubiquitination and supposedly decreases the interaction between GKAP and the other scaffold protein SHANK1, thereby inhibiting growth of dendritic spine heads in rat hippocampal neurons [90]. However, knockout of TRIM3 in mice does not influence on the GKAP or SHANK1 levels. TRIM3 can polyubiquitinate γ-actin and regulates the timing of hippocampal plasticity, learning, and memory [91]. Moreover, the expression of TRIM3 is regulated in p53-dependent manner after the treatment with antagonist of Gamma-Aminobutyric Acid GABA(A) receptor [GABA(A)R] signaling. In turn, TRIM3 regulates the presence of GABA(A)Rs with γ2-subunit at the cell surface and thereby can mediate susceptibility to seizure in mice model of epilepsy [92].

TRIM32 determines cell fate in NSCs and affects the equilibrium between stem cell maintenance and neuronal differentiation, as well as controls the production of olfactory bulb neurons in adults [93 –96]. Loss of TRIM32 alters the behavior in the open field test, but does not influence exploratory and anxiety-related behavior as well as spatial learning [97]. TRIM32 is asymmetrically distributed in dividing NPCs, promotes the degradation of c-MYC by ubiquitination, enhances neuronal differentiation, and suppresses self-renewal [95].

In addition, TRIM32 forms complex with Argonaute-1 (Ago1) and microRNAs by NHL domain. It was shown that TRIM32 expression activates Let-7a as well as some other miRNAs [95]. Also, TRIM32 binds to the RNA helicase DEAD Box Polypeptide (DDX)6, Ago2, and RNA-binding protein Pumilio 1 (Pum1) in vivo. This complex is supposedly involved in let-7a miRNA activation during NSC differentiation [93]. TRIM32 can promote the enhancement of neural differentiation by interacting with retinoic acid receptor α and by increasing its downstream activity in the presence of retinoic acid [94].

TRIM71 modulates the neural differentiation, but does not regulate pluripotency. The loss of TRIM71 in Trim71(−/−) mESCs promotes the expression of neural markers and upregulation of several miRNA (let-7e, mir-132, mir24–2, mir-200) and directs mESCs toward neural differentiation [46]. In addition, mouse TRIM71 is negatively regulated by let-7 miRNA resulting in the correct neural tube closure during embryogenesis [48]. TRIM71 is likely not essential for adult neurogenesis and is found only in the ependymal cells lining the walls of the four ventricles [65].

In summary, the existing data show the important role of TRIMs in the CNS processes both in NSCs and in different types of terminally differentiated neurons. Their functions in CNS may be mediated either by the RING or by the C-terminal domains.

TRIMs in Neuropathology

Compelling evidences point to the essential role of many TRIMs both in immune system and in the development and functioning of CNS. It is therefore not surprising that there is a relationship between alterations of expression of these genes and various neuropathologies. Several data indicate that an expression of some TRIMs in brain is affected by viral infection. For example, rabies virus infection in mice results in the downregulation of TRIM9, as well as in the accumulation of synaptic vesicles in the presynaptic neurons [98]. Japanese encephalitis virus infection increases the expression of TRIM21 in human microglial (CHME3) cells [99].

During the last few years, a lot of data have emerged that indicate that innate immunity is an active player in the neurodegeneration processes [100]. Several genetic alterations associated with neurodegeneration were shown to increase the innate immunity response [101]. It becomes clear that chronic neuroinflammation as an attribute of innate immunity plays an important role in the processes of different neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD) [102 –105]. Neurodegenerative diseases are manifested by the degeneration and death of the specific neurons in the brain, and the inflammation may greatly contribute to their degeneration. Consistent with known neuronal functions, including protective ones, defects in TRIM proteins or alterations of their expression are associated with different neurological pathologies (Table 4). Below, we consider in more detail the existing evidence of the involvement of TRIM proteins in the PD, AD, and HD.

Table 4.

Tripartite Motif Proteins Associated with Neuropathology

TRIM proteins	Neuropathology
TRIM1	Transcription of the gene differs in PD patient-derived iPSCs, neuronal progenitors and neurons in comparison with control cells [106].
TRIM2	Loss-of-function mutations in the gene are a cause of childhood-onset axonal neuropathy [107]. Transcription of the gene differs in PD patient-derived iPSCs, neuronal progenitors, and neurons in comparison with control cells [106].
TRIM4	Increased in NSCs derived from hESCs of HD patients compared with those of healthy patients [108].
TRIM5	Associated with multiple sclerosis [109].
TRIM6	Transcription of the gene differs in PD patient-derived iPSCs, neuronal progenitors, and neurons in comparison with control cells [106].
TRIM8	Epileptic encephalopathy-associated gene [110,111].
TRIM9	Decreased in the affected brain areas in PD and dementia with Lewy bodies [112]. Transcription of the gene differs in PD patient-derived iPSCs, neuronal progenitors and neurons in comparison with control cells [106]. Associated with paraneoplastic neurological syndromes [113].
TRIM10	Single nucleotide polymorphism is associated with PD [114]. The knockdown of TRIM10 decreases MPTP-caused apoptosis and neurotoxicity in PC12 cells through DUSP6 ubiquitination and subsequent degradation [115].
TRIM11	Binds and destabilizes Humanin, a neuroprotective peptide against AD-related insults [116].
TRIM14	Transcription of the gene differs in PD patient-derived iPSCs, neuronal progenitors, and neurons in comparison with control cells [106].
TRIM15	Single nucleotide polymorphism is associated with AD [117].
TRIM16	Transcription of the gene differs in PD patient-derived iPSCs, neuronal progenitors and neurons in comparison with control cells [106].
TRIM17	Decreases the TRIM41-mediated degradation of ZSCAN21 (stimulates α-synuclein transcription in neuronal cells). Infrequent genetic variants of the TRIM17 are associated with PD [118].
TRIM19	Transcription of the gene differs in PD patient-derived iPSCs, neuronal progenitors, and neurons in comparison with control cells [106].
TRIM22	Associated with autism spectrum disorder [119] and multiple sclerosis [109].
TRIM24	Is increased in the blood of MPTP-induced PD in monkeys [120]. Mutations are associated with PD pathogenesis [121]. Transcription of the gene differs in PD patient-derived iPSCs, neuronal progenitors, and neurons in comparison with control cells [106].
TRIM26	Mutations are associated with schizophrenia [122] and with major neuropsychiatric disorders [123].
TRIM27	Upregulated in patients with PD. Induced in the substantia nigra of a MPTP-generated mouse model of PD [124].
TRIM32	Regulates hyperactivity and the development of anxiety and depression disorders induced by chronic stress [125]. Associated with autism spectrum disorder [126], with spinal cord injury [127] and with AD [128]. Transcription of the gene differs in PD patient-derived iPSCs, neuronal progenitors, and neurons in comparison with control cells [106]. Regulates the transcription of the one of the major risk genes of PD, encoding α-synuclein [129]. Suppresses the miRNA, which inhibits the LRRK2, one of the well-known factors associated with PD [130]. Knockdown of TRIM32 protects from ischemia/reperfusion injury to the brain [131].
TRIM34	Hypermethylation is associated with PD [132].
TRIM35	Mutations are associated with AD [133].
TRIM36	Mutations are associated with autosomal recessive anencephaly characterized by the absence of brain tissue and cranium [134].
TRIM37	Altered expression in AD brains [128]. Transcription of the gene differs in PD patient-derived iPSCs, neuronal progenitors, and neurons in comparison with control cells [106].
TRIM41	Mediates degradation of ZSCAN21 thereby modulating α-synuclein transcription in neuronal cells, infrequent genetic variants of the TRIM41 is associated with PD [118].
TRIM46	Associated with paraneoplastic neurological syndromes [135].
TRIM59	The aging-correlated hypermethylation of the gene is associated with abnormalities in DNA repair and cell cycle control and influences cell death signaling in familial early onset AD patient-derived fibroblasts and reprogrammed neurons [136].
TRIM67	Associated with paraneoplastic neurological syndromes [113].
TRIM71	Mutation is associated with congenital hydrocephalus [137,138].
TRIM72	Facilitates repair of ischemia/reperfusion injury to the brain [139].

AD, Alzheimer's disease; DUSP6, dual specificity phosphatase 6; HD, Huntington's disease; hESC, human embryonic stem cell; LRRK, Leucine-Rich Repeat Kinase; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; PD, Parkinson's disease.

TRIMs' involvement in PD pathogenesis

PD results in the death of dopaminergic neurons in the substantia nigra. The immune system plays a significant role in the pathogenesis and progression of PD through inflammation and autoimmune reactions [140,141]. In particular, different TRIMs were found to be associated with PD (Table 4). The level of the TRIM9 is decreased in the affected brain areas upon PD and dementia with Lewy bodies [112]. In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-generated cellular model of PD in PC12 cells, TRIM10 promotes dual specificity phosphatase 6 (DUSP6) ubiquitination and inhibits its expression. The knockdown of TRIM10 decreases MPTP-caused apoptosis and neurotoxicity in PC12 cells [115]. Also, TRIM24 expression was significantly changed in the blood of MPTP-treated monkeys [120]. In addition, TRIM24 was identified among genes with de novo mutations associated with PD pathogenesis [121].

TRIM32 regulates the transcription of one of the major risk genes of PD, encoding α-synuclein [129]. TRIM32 also suppresses the miRNA, which inhibits the Leucine-Rich Repeat Kinase (LRRK)2, one of the well-known factors associated with PD [130]. The expression of TRIM27 gene is increased in the patients with PD as well as in the substantia nigra of mice with MPTP-generated model of PD. At the same time, Trim27 knockout reduces the loss of dopaminergic neurons in MPTP-treated mice [124]. The E3-ubiquitin ligases, TRIM17 and TRIM41, modulate α-synuclein expression and thus may contribute to the pathogenesis of PD. In addition, infrequent allelic variants of the TRIM17 and TRIM41 genes were associated with some familial forms of PD [118].

A relatively new technology for studying molecular mechanisms of PD is the use of human iPSCs, allowing to compare cells from PD patients and from healthy donors. iPSCs derived from fibroblasts of patients with PD and the corresponding neural progenitors and neuronal cultures (enriched with dopaminergic neurons) allow to identify the dysfunctional pathways at the early stages of the disease [142,143]. In this way, the expression of 15 TRIM-encoding genes in the iPSCs derived from PD patients with hereditary and sporadic forms of disease was recently analyzed. The expression of more than half of these genes appears to be altered in PD patients, as compared with healthy individuals, upon reprogramming of fibroblasts into iPSCs and their subsequent neuronal differentiation [106]. These data support an association of multiple TRIM genes (TRIM1, TRIM2, TRIM6, TRIM9, TRIM14, TRIM16, TRIM24, TRIM32, and TRIM37) with PD at the early stages of disease (Table 4).

TRIMs' involvement in AD pathogenesis

Numerous data indicate the relationship of AD with immune system impairments [144]. Inflammation may contribute to AD pathogenesis and promote its progression. Upon AD, the oligomeric forms of beta-amyloid are accumulated in neurons. Their deposition in synapses seems to cause the memory loss in AD [145]. Current data suppose that microglia, which represents the innate immune cells in brain, becomes activated in response to the oligomeric forms of beta-amyloid. The resulting microgliosis is suggested to promote AD development [144].

Some TRIMs (TRIM15, TRIM35, TRIM32, and TRIM37) are supposedly associated with AD pathogenesis and progression [117,128,133] (Table 4). TRIM2 is one of the target genes of miR-9 and miR-181 miRNAs that are known to be downregulated upon AD [146]. TRIM11 promotes the degradation of humanin, a neuroprotective peptide, which was shown to suppress AD-related neurotoxicity [116]. The hypermethylation of TRIM59 potentially contributes to apoptosis upon AD [136] (Table 4). Yet, it is evident that the potential causative role of TRIMs in the AD and PD pathogenesis is not firmly established and awaits further studies.

TRIMs' involvement in HD pathogenesis

HD is a neurodegenerative disease caused by genetic defect in the gene encoding for huntingtin (HTT). The disorder is characterized by motor and cognitive dysfunction. Feyeux et al. [108] searched for genes associated with mutations in HTT gene using the hESC lines derived from embryos with a mutant-HTT allele and from healthy donors. TRIM4 was identified among genes, which were differentially expressed in HD cells (hESCs and corresponding NSCs) compared with wild-type cells. The expression of TRIM4 (at mRNA and protein levels) was shown to be upregulated [108].

Conclusion

Complex structural composition and diversity of functions result in many faces of TRIM proteins not only in the immune response to various pathogens but also in the stem cells' maintenance and differentiation, including neurogenesis. These common pathways brightly illustrate the intimate links between immune and nervous systems.

Footnotes

Author Disclosure Statement

No competing financial interests exist.

Funding Information

This study was funded by the Russian Foundation for Basic Research (grants no. 17-29-06008, 18-04-00733, 19-29-04080), Program for Molecular and Cellular Biology from Presidium of Russian Academy of Sciences (no. 01201356275), Russian Fundamental Scientific Research Program (no. 01201355481).

References

Reymond

, Meroni

, Fantozzi

, Merla

, Cairo

, Luzi

, Riganelli

, Zanaria

, Messali

, et al. (2001). The tripartite motif family identifies cell compartments. EMBO J, 20:2140–2151.

Esposito

, Koliopoulos

and Rittinger

. (2017). Structural determinants of TRIM protein function. Biochem Soc Trans, 45:183–191.

Chu

and Yang

. (2011). SUMO E3 ligase activity of TRIM proteins. Oncogene, 30:1108–1116.

Noguchi

, Okumura

, Takahashi

, Kataoka

, Kamiyama

, Todo

and Hatakeyama

. (2011). TRIM40 promotes neddylation of IKKgamma and is downregulated in gastrointestinal cancers. Carcinogenesis, 32:995–1004.

D'Cruz

, Babon

, Norton

, Nicola

and Nicholson

. (2013). Structure and function of the SPRY/B30.2 domain proteins involved in innate immunity. Protein Sci, 22:1–10.

Short

and Cox

. (2006). Subclassification of the RBCC/TRIM superfamily reveals a novel motif necessary for microtubule binding. J Biol Chem, 281:8970–8980.

Skerra

. (2000). Engineered protein scaffolds for molecular recognition. J Mol Recognit, 13:167–187.

Herquel

, Ouararhni

and Davidson

. (2011). The TIF1α-related TRIM cofactors couple chromatin modifications to transcriptional regulation, signaling and tumor suppression. Transcription, 2:231–236.

Sparrer

KMJ

, Gableske

, Zurenski

, Parker

, Full

, Baumgart

, Kato

, Pacheco-Rodriguez

, Liang

, et al. (2017). TRIM23 mediates virus-induced autophagy via activation of TBK1. Nat Microbiol, 2:1543–1557.

10.

Tocchini

and Ciosk

. (2015). TRIM-NHL proteins in development and disease. Semin Cell Dev Biol, 47–48:52–59.

11.

Ozato

, Shin

, Chang

and Morse

3rd . (2008). TRIM family proteins and their emerging roles in innate immunity. Nat Rev Immunol, 8:849–860.

12.

Versteeg

, Benke

, García-Sastre

and Rajsbaum

. (2014). InTRIMsic immunity: positive and negative regulation of immune signaling by tripartite motif proteins. Cytokine Growth Factor Rev, 25:563–576.

13.

Watanabe

and Hatakeyama

. (2017). TRIM proteins and diseases. J Biochem, 161:135–144.

14.

Zhou

, Jia

, Xue

, Dou

, Ma

, Zhao

, Jiang

, He

, Jin

and Wang

. (2014). TRIM14 is a mitochondrial adaptor that facilitates retinoic acid-inducible gene-I-like receptor-mediated innate immune response. Proc Natl Acad Sci U S A, 111:E245–E254.

15.

Bell

, Malyukova

, Kavallaris

, Marshall

and Cheung

. (2013). TRIM16 inhibits neuroblastoma cell proliferation through cell cycle regulation and dynamic nuclear localization. Cell Cycle, 12:889–898.

16.

Hatakeyama

. (2017). TRIM family proteins: roles in autophagy, immunity, and carcinogenesis. Trends Biochem Sci, 42:297–311.

17.

Tarantul

. (2018). Many faces of TRIM family proteins on the field of oncoimmunology. Univ J Oncol, 1:1–37.

18.

Khan

, Khan

, Ali

and Idrees

. (2019). The interplay between viruses and TRIM family proteins. Rev Med Virol, 29:e2028.

19.

Bottermann

and James

. (2018). Intracellular antiviral immunity. Adv Virus Res, 100:309–354.

20.

van Tol

, Hage

, Giraldo

, Bharaj

and Rajsbaum

. (2017). The TRIMendous role of TRIMs in virus-host interactions. Vaccines (Basel), 5:pii:E23.

21.

Yan

and Chen

. (2012). Intrinsic antiviral immunity. Nat Immunol, 13:214–222.

22.

van Gent

, Sparrer

KMJ

and Gack

. (2018). TRIM proteins and their roles in antiviral host defenses. Annu Rev Virol, 5:385–405.

23.

Sato

, Okumura

, Ariga

and Hatakeyama

. (2012). TRIM6 interacts with Myc and maintains the pluripotency of mouse embryonic stem cells. J Cell Sci, 125:1544–1555.

24.

Novosadova

, Manuilova

, Arsen'eva

, Khaidarova

, Dolotov

, Inozemtseva

, Kozachenkov

, Tarantul

and Grivennikov

. (2005). Different effects of enhanced and reduced expression of pub gene on the formation of embryoid bodies by cultured embryonic mouse stem cell. Bull Exp Biol Med, 140:153–158.

25.

Novosadova

, Manuilova

, Arsenieva

, Lebedev

, Khaidarova

, Tarantul

and Grivennikov

. (2009). Influence of pub gene expression on differentiation of mouse embryonic stem cells into derivatives of ecto-, meso-, and endoderm in vitro. Acta Naturae, 1:93–97.

26.

Kwon

, Yi

, Eichelbaum

, Föhr

, Fischer

, You

, Castello

, Krijgsveld

, Hentze

and Kim

. (2013). The RNA-binding protein repertoire of embryonic stem cells. Nat Struct Mol Biol, 20:1122–1130.

27.

Choudhury

, Heikel

, Trubitsyna

, Kubik

, Nowak

, Webb

, Granneman

, Spanos

, Rappsilber

, Castello

and Michlewski

. (2017). RNA-binding activity of TRIM25 is mediated by its PRY/SPRY domain and is required for ubiquitination. BMC Biol, 15:105.

28.

Choudhury

, Nowak

, Zuo

, Rappsilber

, Spoel

and Michlewski

. (2014). Trim25 is an RNA-specific activator of Lin28a/TuT4-mediated uridylation. Cell Rep, 9:1265–1272.

29.

Zhao

, Zhang

, Cun

, Li

, Liu

, Gao

, Zhu

, Zhou

, Zhang

and Zheng

. (2018). Mouse embryonic stem cells have increased capacity for replication fork restart driven by the specific Filia-Floped protein complex. Cell Res, 28:69–89.

30.

Zhao

, Li

, Ayers

, Gu

, Shi

, Zhu

, Chen

, Wang

and Wang

. (2013). Jmjd3 inhibits reprogramming by upregulating expression of INK4a/Arf and targeting PHF20 for ubiquitination. Cell, 152:1037–1050.

31.

Okumura

, Okumura

, Matsumoto

, Nakayama

and Hatakeyama

. (2011). TRIM8 regulates Nanog via Hsp90β-mediated nuclear translocation of STAT3 in embryonic stem cells. Biochim Biophys Acta, 1813:1784–1792.

32.

Rafiee

, Girardot

, Sigismondo

and Krijgsveld

. (2016). Expanding the circuitry of pluripotency by selective isolation of chromatin-associated proteins. Mol Cell, 64:624–635.

33.

Jain

, Allton

, Iacovino

, Mahen

, Milczarek

, Zwaka

, Kyba

and Barton

. (2012). p53 regulates cell cycle and microRNAs to promote differentiation of human embryonic stem cells. PLoS Biol, 10:e1001268.

34.

Quenneville

, Turelli

, Bojkowska

, Raclot

, Offner

, Kapopoulou

and Trono

. (2012). The KRAB-ZFP/KAP1 system contributes to the early embryonic establishment of site-specific DNA methylation patterns maintained during development. Cell Rep, 2:766–773.

35.

Seki

, Kurisaki

, Watanabe-Susaki

, Nakajima

, Nakanishi

, Arai

, Shiota

, Sugino

and Asashima

. (2010). TIF1beta regulates the pluripotency of embryonic stem cells in a phosphorylation-dependent manner. Proc Nat Acad Sci U S A, 107:10926–10931.

36.

Oleksiewicz

, Gładych

, Raman

, Heyn

, Mereu

, Chlebanowska

, Andrzejewska

, Sozańska

, Samant

, et al. (2017). TRIM28 and interacting KRAB-ZNFs control self-renewal of human pluripotent stem cells through epigenetic repression of pro-differentiation genes. Stem Cell Reports, 9:2065–2080.

37.

, Wang

, Zaromytidou

, Zhang

, Chow-Tsang

, Liu

, Kim

, Barlas

, Manova-Todorova

, et al. (2011). A poised chromatin platform for TGF-β access to master regulators. Cell, 147:1511–1524.

38.

Allton

, Jain

, Herz

, Tsai

, Jung

, Qin

, Bergmann

, Johnson

and Barton

. (2009). Trim24 targets endogenous p53 for degradation. Proc Natl Acad Sci U S A, 106:11612–11616.

39.

Ivanov

, Peng

, Yurchenko

, Yap

, Negorev

, Schultz

, Psulkowski

, Fredericks

, White

, et al. (2007). PHD domain-mediated E3 ligase activity directs intramolecular sumoylation of an adjacent bromodomain required for gene silencing. Mol Cell, 28:823–837.

40.

Elsässer

, Noh

, Diaz

, Allis

and Banaszynski

. (2015). Histone H3.3 is required for endogenous retroviral element silencing in embryonic stem cells. Nature, 522:240–244.

41.

Turelli

, Castro-Diaz

, Marzetta

, Kapopoulou

, Raclot

, Duc

, Tieng

, Quenneville

and Trono

. (2014). Interplay of TRIM28 and DNA methylation in controlling human endogenous retroelements. Genome Res, 24:1260–1270.

42.

Tao

, Yen

, Chitiashvili

, Nakano

, Kim

, Hosohama

, Tan

, Nakano

, Chen

and Clark

. (2018). TRIM28-regulated transposon repression is required for human germline competency and not primed or naive human pluripotency. Stem Cell Reports, 10:243–256.

43.

Klimczak

, Czerwińska

, Mazurek

, Sozańska

, Biecek

, Mackiewicz

and Wiznerowicz

. (2017) TRIM28 epigenetic corepressor is indispensable for stable induced pluripotent stem cell formation. Stem Cell Res, 23:163–172.

44.

Miles

, de Vries

, Gisler

, Lieftink

, Akhtar

, Gogola

, Pawlitzky

, Hulsman

, Tanger

, et al. (2017). TRIM28 is an epigenetic barrier to induced pluripotent stem cell reprogramming. Stem Cells, 35:147–157.

45.

Xia

, Zuo

, Luo

, Sun

, Bai

and Xi

. (2017). Role of TRIM33 in Wnt signaling during mesendoderm differentiation. Sci China Life Sci, 60:1142–1149.

46.

Rajderkar

, Panaretos

and Kaartinen

. (2017). Trim33 regulates early maturation of mouse embryoid bodies in vitro. Biochem Biophys Rep, 12:185–192.

47.

Chang

, Martinez

, Thornton

, Hagan

, Nguyen

and Gregory

. (2012). Trim71 cooperates with microRNAs to repress Cdkn1a expression and promote embryonic stem cell proliferation. Nat Commun, 3:923.

48.

Mitschka

, Ulas

, Goller

, Schneider

, Egert

, Mertens

, Brüstle

, Schorle

, Beyer

, et al. (2015). Co-existence of intact stemness and priming of neural differentiation programs in mES cells lacking Trim71. Sci Rep, 5:11126.

49.

, Duan

, Zhao

, Gu

, Liao

, Su

, Hao

, Zhang

, Yang

and Wang

. (2019). A TRIM71 binding long noncoding RNA Trincr1 represses FGF/ERK signaling in embryonic stem cells. Nat Commun, 10:1368.

50.

Nguyen

DTT

, Richter

, Michel

, Mitschka

, Kolanus

, Cuevas

and Gregory Wulczyn

. (2017). The ubiquitin ligase LIN41/TRIM71 targets p53 to antagonize cell death and differentiation pathways during stem cell differentiation. Cell Death Differ, 24:1063–1078.

51.

Lin

, Hsieh

, Kuo

, Yu

, Kuo

, Lo

, Lin

, Yu

and Li

. (2007). Human TRIM71 and its nematode homologue are targets of let-7 microRNA and its zebrafish orthologue is essential for development. Mol Biol Evol, 24:2525–2534.

52.

Rybak

, Fuchs

, Hadian

, Smirnova

, Wulczyn

, Michel

, Nitsch

, Krappmann

and Wulczyn

. (2009). The let-7 target gene mouse lin-41 is a stem cell specific E3 ubiquitin ligase for the miRNA pathway protein Ago2. Nat Cell Biol, 11:1411–1420.

53.

Worringer

, Rand

, Hayashi

, Sami

, Takahashi

, Tanabe

, Narita

, Srivastava

and Yamanaka

. (2014). The let-7/LIN-41 pathway regulates reprogramming to human induced pluripotent stem cells by controlling expression of prodifferentiation genes. Cell Stem Cell, 14:40–52.

54.

Bahnassawy

, Perumal

, Gonzalez-Cano

, Hillje

, Taher

, Makalowski

, Suzuki

, Fuellen

, del Sol

and Schwamborn

. (2015). TRIM32 modulates pluripotency entry and exit by directly regulating Oct4 stability. Sci Rep, 5:13456.

55.

Olson

, Oh

and Houston

. (2015). The dynamics of plus end polarization and microtubule assembly during Xenopus cortical rotation. Dev Biol, 401:249–263.

56.

Cuykendall

and Houston

. (2009). Vegetally localized Xenopus trim36 regulates cortical rotation and dorsal axis formation. Development, 136:3057–3065.

57.

Sampath Kumar

, Seah

, Ling

, Wang

, Tan

, Nitsch

, Lim

, Lorthongpanich

, Wollmann

, et al. (2017). Loss of maternal Trim28 causes male-predominant early embryonic lethality. Genes Dev, 31:12–17.

58.

Morsut

, Yan

, Enzo

, Aragona

, Soligo

, Wendling

, Mark

, Khetchoumian

, Bressan

, et al. (2010). Negative control of Smad activity by ectodermin/Tif1gamma patterns the mammalian embryo. Development, 137:2571–2578.

59.

, Wu

, Ye

, Zeng

, Zhang

, Che

, Zhang

, Liu

, Lin

and Yang

. (2018). Embryonic lethality in mice lacking Trim59 due to impaired gastrulation development. Cell Death Dis, 9:302.

60.

Cuevas

, Rybak-Wolf

, Rohde

, Nguyen

and Wulczyn

. (2015). Lin41/Trim71 is essential for mouse development and specifically expressed in postnatal ependymal cells of the brain. Front Cell Dev Biol, 3:20.

61.

Maller Schulman

, Liang

, Stahlhut

, DelConte

, Stefani

and Slack

. (2008). The let-7 microRNA target gene, Mlin41/Trim71 is required for mouse embryonic survival and neural tube closure. Cell Cycle, 7:3935–3942.

62.

Yoshigai

, Kawamura

, Kuhara

and Tashiro

. (2009). Trim36/Haprin plays a critical role in the arrangement of somites during Xenopus embryogenesis. Biochem Biophys Res Commun, 378:428–432.

63.

Han

, Wang

, Zhao

, Han

, Zong

, Miao

, Song

and Wang

. (2016). Trim69 regulates zebrafish brain development by ap-1 pathway. Sci Rep, 6:24034.

64.

Tuoc

and Stoykova

. (2008). Trim11 modulates the function of neurogenic transcription factor Pax6 through ubiquitin-proteosome system. Genes Dev, 22:1972–1986.

65.

Berti

, Messali

, Ballabio

, Reymond

and Meroni

. (2002). TRIM9 is specifically expressed in the embryonic and adult nervous system. Mech Dev, 113:159–162.

66.

Winkle

, Olsen

, Kim

, Moy

, Song

and Gupton

. (2016). Trim9 deletion alters the morphogenesis of developing and adult-born hippocampal neurons and impairs spatial learning and memory. J Neurosci, 36:4940–4958.

67.

Winkle

, McClain

, Valtschanoff

, Park

, Maglione

and Gupton

. (2014). A novel Netrin-1-sensitive mechanism promotes local SNARE-mediated exocytosis during axon branching. J Cell Biol, 205:217–232.

68.

Plooster

, Menon

, Winkle

, Urbina

, Monkiewicz

, Phend

, Weinberg

and Gupton

. (2017). TRIM9-dependent ubiquitination of DCC constrains kinase signaling, exocytosis, and axon branching. Mol Biol Cell, 28:2374–2385.

69.

Menon

, Boyer

, Winkle

, McClain

, Hanlin

, Pandey

, Rothenfußer

, Taylor

and Gupton

. (2015). The E3 ubiquitin ligase TRIM9 is a filopodia off switch required for netrin-dependent axon guidance. Dev Cell, 35:698–712.

70.

van Beuningen

SFB

, Will

, Harterink

, Chazeau

, van Battum

, Frias

, Franker

MAM

, Katrukha

, Stucchi

, et al. (2015). TRIM46 controls neuronal polarity and axon specification by driving the formation of parallel microtubule arrays. Neuron, 88:1208–1226.

71.

Yaguchi

, Okumura

, Takahashi

, Kano

, Kameda

, Uchigashima

, Tanaka

, Watanabe

, Sasaki

and Hatakeyama

. (2012). TRIM67 protein negatively regulates Ras activity through degradation of 80K-H and induces neuritogenesis. J Biol Chem, 287:12050–12059.

72.

Boyer

, Monkiewicz

, Menon

, Moy

and Gupton

. (2018). Mammalian TRIM67 functions in brain development and behavior. eNeuro, 5:pii:ENEURO.0186-18.2018.

73.

Montell

. (2019). TRIMing neural connections with ubiquitin. Dev Cell, 48:5–6.

74.

Hong

, Chae

, Lardaro

, Hong

and Kim

. (2008). Trim11 increases expression of dopamine beta-hydroxylase gene by interacting with Phox2b. Biochem Biophys Res Commun, 368:650–655.

75.

Magiera

, Mora

, Mojsa

, Robbins

, Lassot

and Desagher

. (2013). Trim17-mediated ubiquitination and degradation of Mcl-1 initiate apoptosis in neurons. Cell Death Differ, 20:281–292.

76.

Mojsa

, Mora

, Bossowski

, Lassot

and Desagher

. (2015). Control of neuronal apoptosis by reciprocal regulation of NFATc3 and Trim17. Cell Death Differ, 22:274–286.

77.

Venuto

, Castellana

, Monti

, Appolloni

, Fusilli

, Fusco

, Pucci

, Malatesta

, Mazza

, Merla

and Micale

. (2019). TRIM8-driven transcriptomic profile of neural stem cells identified glioma-related nodal genes and pathways. Biochim Biophys Acta Gen Subj, 1863:491–501.

78.

Zhang

, Mukherjee

, Tucker-Burden

, Ross

, Chau

, Kong

and Brat

. (2017). TRIM8 regulates stemness in glioblastoma through PIAS3-STAT3. Mol Oncol, 11:280–294.

79.

Boutou

, Matsas

and Mamalaki

. (2001). Isolation of a mouse brain cDNA expressed in developing neuroblasts and mature neurons. Brain Res Mol Brain Res, 86:153–167.

80.

Fasching

, Kapopoulou

, Sachdeva

, Petri

, Jönsson

, Männe

, Turelli

, Jern

, Cammas

, Trono

and Jakobsson

. (2015). TRIM28 represses transcription of endogenous retroviruses in neural progenitor cells. Cell Rep, 10:20–28.

81.

Brattås

, Jönsson

, Fasching

, Nelander Wahlestedt

, Shahsavani

, Falk

, Jern

, Parmar

and Jakobsson

. (2017). TRIM28 controls a gene regulatory network based on endogenous retroviruses in human neural progenitor cells. Cell Rep, 18:1–11.

82.

Grassi

, Jönsson

, Brattås

and Jakobsson

. (2019). TRIM28 and the control of transposable elements in the brain. Brain Res, 1705:43–47.

83.

Falk

, Joosten

, Kaartinen

and Sommer

. (2014). Smad4 and Trim33/Tif1γ redundantly regulate neural stem cells in the developing cortex. Cereb Cortex, 24:2951–2963.

84.

Pavlaki

, Alammari

, Sun

, Clark

, Sirey

, Lee

, Woodcock

, Ponting

, Szele

and Vance

. (2018). The long non-coding RNA Paupar promotes KAP1-dependent chromatin changes and regulates olfactory bulb neurogenesis. EMBO J, 37:pii:e98219.

85.

Jakobsson

, Cordero

, Bisaz

, Groner

, Busskamp

, Bensadoun

, Cammas

, Losson

, Mansuy

, Sandi

and Trono

. (2008). KAP1-mediated epigenetic repression in the forebrain modulates behavioral vulnerability to stress. Neuron, 60:818–831.

86.

Khazaei

, Bunk

, Hillje

, Jahn

, Riegler

, Knoblich

, Young

and Schwamborn

. (2011). The E3-ubiquitin ligase TRIM2 regulates neuronal polarization. J Neurochem, 117:29–37.

87.

Balastik

, Ferraguti

, Pires-da Silva

, Lee

, Alvarez-Bolado

, Lu

and Gruss

. (2008). Deficiency in ubiquitin ligase TRIM2 causes accumulation of neurofilament light chain and neurodegeneration. Proc Natl Acad Sci U S A, 105:12016–12021.

88.

Thompson

, Pearson

, Ashley

, Jessick

, Murphy

, Gafken

, Henshall

, Morris

, Simon

and Meller

. (2011). Identification of a novel Bcl-2-interacting mediator of cell death (Bim) E3 ligase, tripartite motif-containing protein 2 (TRIM2), and its role in rapid ischemictolerance-induced neuroprotection. J Biol Chem, 286:19331–19339.

89.

Mukherjee

, Tucker-Burden

, Zhang

, Moberg

, Read

, Hadjipanayis

and Brat

. (2016). Drosophila brat and human ortholog TRIM3 maintain stem cell equilibrium and suppress brain tumorigenesis by attenuating Notch nuclear transport. Cancer Res, 76:2443–2452.

90.

Hung

, Sung

, Brito

and Sheng

. (2010). Degradation of postsynaptic scaffold GKAP and regulation of dendritic spine morphology by the TRIM3 ubiquitin ligase in rat hippocampal neurons. PLoS One, 5:e9842.

91.

Schreiber

, Végh

, Dawitz

, Kroon

, Loos

, Labonté

, Li

, Van Nierop

, Van Diepen

, et al. (2015). Ubiquitin ligase TRIM3 controls hippocampal plasticity and learning by regulating synaptic γ-actin levels. J Cell Biol, 211:569–586.

92.

Cheung

, Yang

, Berger

, Zaugg

, Reilly

, Elia

, Wakeham

, You-Ten

, Chang

, et al. (2010). Identification of BERP (brain-expressed RING finger protein) as a p53 target gene that modulates seizure susceptibility through interacting with GABA(A) receptors. Proc Natl Acad Sci U S A, 107:11883–11888.

93.

Nicklas

, Okawa

, Hillje

, González-Cano

, Del Sol

and Schwamborn

. (2015). The RNA helicase DDX6 regulates cell-fate specification in neural stem cells via miRNAs. Nucleic Acids Res, 43:2638–2654.

94.

Sato

, Okumura

, Kano

, Kondo

, Ariga

and Hatakeyama

. (2011). TRIM32 promotes neural differentiation through retinoic acid receptor-mediated transcription. J Cell Sci, 124:3492–3502.

95.

Schwamborn

, Berezikov

and Knoblich

. (2009). The TRIM-NHL protein TRIM32 activates microRNAs and prevents self-renewal in mouse neural progenitors. Cell, 136:913–925.

96.

Hillje

, Pavlou

, Beckmann

, Worlitzer

, Bahnassawy

, Lewejohann

, Palm

and Schwamborn

. (2013). TRIM32-dependent transcription in adult neural progenitor cells regulates neuronal differentiation. Cell Death Dis, 4:e976.

97.

Hillje

, Beckmann

, Pavlou

, Jaeger

, Pacheco

, Sauter

, Schwamborn

and Lewejohann

. (2015). The neural stem cell fate determinant TRIM32 regulates complex behavioral traits. Front Cell Neurosci, 9:75.

98.

Dhingra

, Li

, Liu

and Fu

. (2007). Proteomic profiling reveals that rabies virus infection results in differential expression of host proteins involved in ion homeostasis and synaptic physiology in the central nervous system. J Neurovirol, 13:107–117.

99.

Manocha

, Mishra

, Sharma

, Kumawat

, Basu

and Singh

. (2014). Regulatory role of TRIM21 in the type-I interferon pathway in Japanese encephalitis virus-infected human microglial cells. J Neuroinflammation, 11:24.

100.

Richards

, Robertson

, O'Keefe

, Fornarino

, Scott

, Lardelli

and Baune

. (2016). The enemy within: innate surveillance-mediated cell death, the common mechanism of neurodegenerative disease. Front Neurosci, 10:193.

101.

Gagliano

, Pouget

, Hardy

, Knight

, Barnes

, Ryten

and Weale

. (2016). Genomics implicates adaptive and innate immunity in Alzheimer's and Parkinson's diseases. Ann Clin Transl Neurol, 3:924–933.

102.

Chen

, Zhang

and Huang

. (2016). Role of neuroinflammation in neurodegenerative diseases (review). Mol Med Rep, 13:3391–3396.

103.

Rocha

, Ribeiro

, Furr-Stimming

and Teixeira

. (2016). Neuroimmunology of Huntington's disease: revisiting evidence from human studies. Mediators Inflamm, 2016:8653132.

104.

Fakhoury

. (2015). Role of immunity and inflammation in the pathophysiology of neurodegenerative diseases. Neurodegener Dis, 15:63–69.

105.

Kempuraj

, Thangavel

, Natteru

, Selvakumar

, Saeed

, Zahoor

, Zaheer

, Iyer

and Zaheer

. (2016). Neuroinflammation induces neurodegeneration. J Neurol Neurosurg Spine, 1:pii:1003.

106.

Nenasheva

, Novosadova

, Makarova

, Lebedeva

, Grefenshtein

, Arsenyeva

, Antonov

, Grivennikov

and Tarantul

. (2017). The transcriptional changes of trim genes associated with Parkinson's disease on a model of human induced pluripotent stem cells. Mol Neurobiol, 54:7204–7211.

107.

Ylikallio

, Poyhonen

, Zimon

, De Vriendt

, Hilander

, Paetau

, Jordanova

, Lonnqvist

and Tyynismaa

. (2013). Deficiency of the E3 ubiquitin ligase TRIM2 in early-onset axonal neuropathy. Hum Mol Genet, 22:2975–2983.

108.

Feyeux

, Bourgois-Rocha

, Redfern

, Giles

, Lefort

, Aubert

, Bonnefond

, Bugi

, Ruiz

, et al. (2012). Early transcriptional changes linked to naturally occurring Huntington's disease mutations in neural derivatives of human embryonic stem cells. Hum Mol Genet, 21:3883–3895.

109.

Morris

, Maes

, Murdjeva

and Puri

. (2019). Do human endogenous retroviruses contribute to multiple sclerosis, and if so, how?. Mol Neurobiol, 56:2590–2605.

110.

Sakai

, Fukai

, Matsushita

, Miyake

, Saitsu

, Akamine

, Torio

, Sasazuki

, Ishizaki

, et al. (2016). De novo truncating mutation of TRIM8 causes early-onset epileptic encephalopathy. Ann Hum Genet, 80:235–240.

111.

Assoum

, Lines

, Elpeleg

, Darmency

, Whiting

, Edvardson

, Devinsky

, Heinzen

, Hernan

, et al. (2018). Further delineation of the clinical spectrum of de novo TRIM8 truncating mutations. Am J Med Genet A, 176:2470–2478.

112.

Tanji

, Kamitani

, Mori

, Kakita

, Takahashi

and Wakabayashi

. (2010). TRIM9, a novel brain-specific E3 ubiquitin ligase, is repressed in the brain of Parkinson's disease and dementia with Lewy bodies. Neurobiol Dis, 38:210–218.

113.

, Gupton

, Tanji

, Bastien

, Brugière

, Couté

, Quadrio

, Rogemond

, Fabien

, Desestret

and Honnorat

. (2019). TRIM9 and TRIM67 are new targets in paraneoplastic cerebellar degeneration. Cerebellum, 18:245–254.

114.

Witoelar

, Jansen

, Wang

, Desikan

, Gibbs

, Blauwendraat

, Thompson

, Hernandez

, Djurovic

, et al. (2017). Genome-wide pleiotropy between Parkinson disease and autoimmune diseases. JAMA Neurol, 74:780–792.

115.

Huang

, Zhu

and Xu

. (2019). Silencing of TRIM10 alleviates apoptosis in cellular model of Parkinson's disease. Biochem Biophys Res Commun, 518:451–458.

116.

Niikura

, Hashimoto

, Tajima

, Ishizaka

, Yamagishi

, Kawasumi

, Nawa

, Terashita

, Aiso

and Nishimoto

. (2003). A tripartite motif protein trim11 binds and destabilizes humanin, a neuroprotective peptide against Alzheimer's disease-relevant insults. Eur J Neurosci, 17:1150–1158.

117.

Shi

, Medway

, Bullock

, Brown

, Kalsheker

and Morgan

. (2010). Analysis of genome-wide association study (GWAS) data looking for replicating signals in Alzheimer's disease (AD). Int J Mol Epidemiol Genet, 1:53–66.

118.

Lassot

, Mora

, Lesage

, Zieba

, Coque

, Condroyer

, Bossowski

, Mojsa

, Marelli

, et al. (2018). The E3 ubiquitin ligases TRIM17 and TRIM41 modulate α-synuclein expression by regulating ZSCAN21. Cell Rep, 25:2484.e9–2496.e9.

119.

Quartier

, Chatrousse

, Redin

, Keime

, Haumesser

, Maglott-Roth

, Brino

, Le Gras

, Benchoua

, Mandel

and Piton

. (2018). Genes and pathways regulated by androgens in human neural cells, potential candidates for the male excess in autism spectrum disorder. Biol Psychiatry, 84:239–252.

120.

Shi

, Huang

, Luo

, Xia

, Liu

, Li

, Liu

, Ma

, Fang

, et al. (2017). Pilot study: molecular risk factors for diagnosing sporadic Parkinson's disease based on gene expression in blood in MPTP-induced rhesus monkeys. Oncotarget, 8:105606–105614.

121.

Guo

, Zhang

, Li

, Mei

, Xue

, Chen

, Tang

, Shen

, Jiang

, et al. (2018). Coding mutations in NUS1 contribute to Parkinson's disease. Proc Natl Acad Sci U S A, 115:11567–11572.

122.

de Jong

, van Eijk

, Zeegers

, Strengman

, Janson

, Veldink

, van den Berg

, Cahn

, Kahn

, Boks

and Ophoff

; PGC Schizophrenia (GWAS) Consortium. (2012). Expression QTL analysis of top loci from GWAS meta-analysis highlights additional schizophrenia candidate genes. Eur J Hum Genet, 20:1004–1008.

123.

Lotan

, Fenckova

, Bralten

, Alttoa

, Dixson

, Williams

and van der Voet

. (2014). Neuroinformatic analyses of common and distinct genetic components associated with major neuropsychiatric disorders. Front Neurosci, 8:331.

124.

Liu

, Zhu

, Lin

, Fan

, Piao

and Jiang

. (2014). Deficiency of Trim27 protects dopaminergic neurons from apoptosis in the neurotoxin model of Parkinson's disease. Brain Res, 1588:17–24.

125.

Ruan

, Wang

, Shen

, Guo

, Yang

, Zhou

, Tan

, Zhou

, Liu

, et al. (2014). Deletion of TRIM32 protects mice from anxiety- and depression-like behaviors under mild stress. Eur J Neurosci, 40:2680–2690.

126.

Lionel

, Tammimies

, Vaags

, Rosenfeld

, Ahn

, Merico

, Noor

, Runke

, Pillalamarri

, et al. (2014). Disruption of the ASTN2/TRIM32 locus at 9q33.1 is a risk factor in males for autism spectrum disorders, ADHD and other neurodevelopmental phenotypes. Hum Mol Genet, 23:2752–2768.

127.

, Zou

, Zhu

, Zhang

, Chen

, Cheng

, Liu

, Ma

and Xu

. (2017). TRIM32 affects the recovery of motor function following spinal cord injury through regulating proliferation of glia. Oncotarget, 8:45380–45390.

128.

Yokota

, Mishra

, Akatsu

, Tani

, Miyauchi

, Yamamoto

, Kosaka

, Nagai

, Sawada

and Heese

. (2006). Brain site-specific gene expression analysis in Alzheimer's disease patients. Eur J Clin Invest, 36:820–830.

129.

Pavlou

MAS

, Colombo

, Fuertes-Alvarez

, Nicklas

, Cano

, Marín

, Goncalves

and Schwamborn

. (2017). Expression of the Parkinson's disease-associated gene alpha-synuclein is regulated by the neuronal cell fate determinant TRIM32. Mol Neurobiol, 54:4257–4270.

130.

Gonzalez-Cano

, Menzl

, Tisserand

, Nicklas

and Schwamborn

. (2018). Parkinson's disease-associated mutant LRRK2-mediated inhibition of miRNA activity is antagonized by TRIM32. Mol Neurobiol, 55:3490–3498.

131.

Wei

, Zhang

, Ji

, Xu

, Zhao

, Zhang

, Pang

, Zhang

, Yang

and Ma

. (2019). Knockdown of TRIM32 protects hippocampal neurons from oxygen-glucose deprivation-induced injury. Neurochem Res, 44:2182–2189.

132.

Kaut

, Schmitt

, Tost

, Busato

, Liu

, Hofmann

, Witt

, Rietschel

, Fröhlich

and Wüllner

. (2017). Epigenome-wide DNA methylation analysis in siblings and monozygotic twins discordant for sporadic Parkinson's disease revealed different epigenetic patterns in peripheral blood mononuclear cells. Neurogenetics, 18:7–22.

133.

Logue

, Lancour

, Farrell

, Simkina

, Fallin

, Lunetta

and Farrer

. (2018). Targeted sequencing of Alzheimer disease genes in African Americans implicates novel risk variants. Front Neurosci, 12:592.

134.

Singh

, Kumble Bhat

, Tiwari

, Kodaganur

, Tontanahal

, Sarda

, Malini

and Kumar

. (2017). A homozygous mutation in TRIM36 causes autosomal recessive anencephaly in an Indian family. Hum Mol Genet, 26:1104–1114.

135.

van Coevorden-Hameete

, van Beuningen

SFB

, Perrenoud

, Will

, Hulsenboom

, Demonet

, Sabater

, Kros

, Verschuuren

JJGM

, et al. (2017). Antibodies to TRIM46 are associated with paraneoplastic neurological syndromes. Ann Clin Transl Neurol, 4:680–686.

136.

Wezyk

, Spólnicka

, Pośpiech

, Pepłońska

, Zbieć-Piekarska

, Ilkowski

, Styczyńska

, Barczak

, Zboch

, et al. (2018). Hypermethylation of TRIM59 and KLF14 influences cell death signaling in familial Alzheimer's disease. Oxid Med Cell Longev, 2018:6918797.

137.

Furey

, Choi

, Jin

, Zeng

, Timberlake

, Nelson-Williams

, Mansuri

, Lu

, Duran

, et al. (2018). De novo mutation in genes regulating neural stem cell fate in human congenital hydrocephalus. Neuron, 99:302.e4–314.e4.

138.

Duy

, Furey

and Kahle

. (2019). Trim71/lin-41 links an ancient miRNA pathway to human congenital hydrocephalus. Trends Mol Med, 25:467–469.

139.

Yao

, Zhang

, Zhu

, Li

, Han

, Chen

, Wang

, Zeng

, Liu

, et al. (2016). MG53 permeates through blood-brain barrier to protect ischemic brain injury. Oncotarget, 7:22474–22485.

140.

De Virgilio

, Greco

, Fabbrini

, Inghilleri

, Rizzo

, Gallo

, Conte

, Rosato

, Ciniglio Appiani

and de Vincentiis

. (2016). Parkinson's disease: autoimmunity and neuroinflammation. Autoimmun Rev, 15:1005–1011.

141.

Lee

, James

and Cowley

. (2017). LRRK2 in peripheral and central nervous system innate immunity: its link to Parkinson's disease. Biochem Soc Trans, 45:131–139.

142.

Beevers

, Caffrey

and Wade-Martins

. (2013). Induced pluripotent stem cell (iPSC)-derived dopaminergic models of Parkinson's disease. Biochem Soc Trans, 41:1503–1508.

143.

Sánchez-Danés

, Richaud-Patin

, Carballo-Carbajal

, Jiménez-Delgado

, Caig

, Mora

, Di Guglielmo

, Ezquerra

, Patel

, et al. (2012). Disease-specific phenotypes in dopamine neurons from human iPS-based models of genetic and sporadic Parkinson's disease. EMBO Mol Med, 4:380–395.

144.

Vanitallie

. (2017). Alzheimer's disease: innate immunity gone awry?. Metabolism, 69S:S41–S49.

145.

Hong

, Beja-Glasser

, Nfonoyim

, Frouin

, Li

, Ramakrishnan

, Merry

, Shi

, Rosenthal

, et al. (2016). Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science, 352:712–716.

146.

Schonrock

, Humphreys

, Preiss

and Götz

. (2012). Target gene repression mediated by miRNAs miR-181c and miR-9 both of which are down-regulated by amyloid-β. J Mol Neurosci, 46:324–335.