Exposure of phosphatidylserine by Xk-related protein family members during apoptosis [Membrane Biology]

September 17th, 2014 by Suzuki, J., Imanishi, E., Nagata, S.

Apoptotic cells expose phosphatidylserine (PtdSer) on their surface as an eat me signal. Mammalian Xk-related (Xkr) protein 8, which is predicted to contain 6 transmembrane regions, and its Caenorhabditis elegans homolog CED-8 promote apoptotic PtdSer exposure. The mouse and human Xkr families consist of 8 and 9 members, respectively. Here, we found that mouse Xkr-family members, with the exception of Xkr2, are localized to the plasma membrane. When Xkr8-deficient cells, which do not expose PtdSer during apoptosis, were transformed by mXkr family members, the transformants expressing Xkr4, Xkr8, or Xkr9 responded to apoptotic stimuli by exposing cell-surface PtdSer and were efficiently engulfed by macrophages. Like Xkr8, Xkr4 and Xkr9 were found to possess a caspase-recognition site in the C-terminal region and to require its direct cleavage by caspases for their function. Site-directed mutagenesis of the amino acid residues conserved among CED-8, Xkr4, Xkr8, and Xkr9 identified several essential residues in the second transmembrane and second cytoplasmic regions. Real-time PCR analysis indicated that unlike Xkr8, which is ubiquitously expressed, Xkr4 and Xkr9 expression is tissue-specific.