Serologically Defined Colon Cancer Antigen 3 Is Necessary for the Presentation of TNF Receptor 1 on Cell Surface

Tumor necrosis factor (TNF) induces apoptosis in sensitive cells in culture when used in combination with inhibitors of transcription or translation. We applied the genetic suppressor element (GSE) methodology to search for the genetic elements protecting NIH3T3 cells from TNF-stimulated death. Ten putative GSEs were isolated from TNF-resistant cells, one of which (GSE0-1) corresponded to the cDNA sequence known as the mouse homolog of human serologically defined colon cancer antigen 3 (SDCCAG3). SDCCAG3 protein contains the region similar to the coiled-coil domain of the myosin tail. The same domain is present in the proteins related to the organelles/proteins trafficking, such as kinesin, Golgin-160, and dynein. We proposed that the SDCCAG3 function might be related to protein trafficking and secretion. The expression of the coiledcoil domain as the dominant negative mutant form of SDCCAG3 made the NIH3T3 and HeLa cells resistant to TNF-specific apoptosis. The presentation of TNFR1 at the surface of these cells was reduced, which affected the sensitivity of the cells to the TNF treatment. We recently showed that the inhibition of protein trafficking and secretion depleted the unstable TNFR1 from plasma membrane. The inhibition of SDCCAG3 activity by its dominant negative mutant suppressed the protein trafficking and secretion, and decreased TNFR1 presentation on the cell surface. Based on these results, we presume that SDCCAG3 is important for protein trafficking and presentation of TNFR1 on the cell surface. Therefore, SDCCAG3 can be viewed as a potential target for modulation of TNF response.