FAM83G is a novel apoptosis inducer

The eight members of FAM83 family are mostly uncharacterized proteins. FAM83G is present across vertebrates and a missense mutation in dogs resulted in hereditary footpad hyperkeratosis and a truncation in mice was reported to be responsible for the wooly mutation ( wly ). Through a serine phosphorylation proteomic screen we uncovered that overexpressed FAM83G significantly reduced cell number and this effect was primarily due to activation of apoptotic programmed cell death, characterized by increased DNA fragmentation, mitochondrial release of cytochrome C into the cytosol and changes in the cleavage patterns of PARP, caspase 3 and caspase 7. Surprisingly, this did not require the addition of any stress inducers but simply occurred upon over expression of FAM83G. The ability of FAM83G to activate apoptosis in the absence any stressor requires the phosphorylation of S356 as phosphorylation of this site occurred in FAM83G over expressing cells and mutation of this residue to alanine protected against apoptosis and cell death. Although we have not directly identified the kinase(s) responsible the most likely candidates are PKD1/PKCmu. Moreover, PKD1/PKCmu have been shown to directly phosphorylation S82 of HSP27 that protects cells from apoptosis. In this regard, expression of wild type FAM83G suppressed S82‐HSP27 phosphorylation whereas expression of the S356A‐FAM83G mutant had no effect on S82‐HSP27 phosphorylation. We hypothesize that FAM3G and HSP27 may compete for substrate recognition by PKD1/PKCmu would account for the effects of phosphorylation site peptide to mimic the effect of wild type FAM83G. Further studies are therefore needed to determine whether FAM83G functions as a direct antagonist of PKD1/PKCmu mediated HSP27 phosphorylation. Support or Funding Information None