| First Author | Ueffing N | Year | 2008 |
| Journal | Cell Death Differ | Volume | 15 |
| Issue | 4 | Pages | 773-82 |
| PubMed ID | 18219316 | Mgi Jnum | J:150996 |
| Mgi Id | MGI:3852626 | Doi | 10.1038/sj.cdd.4402314 |
| Citation | Ueffing N, et al. (2008) Mutational analyses of c-FLIPR, the only murine short FLIP isoform, reveal requirements for DISC recruitment. Cell Death Differ 15(4):773-82 |
| abstractText | Cellular FLICE-inhibitory protein (c-FLIP) proteins are known as potent inhibitors of death receptor-mediated apoptosis by interfering with caspase-8 activation at the death-inducing signaling complex (DISC). Among the three human isoforms, c-FLIP(long), c-FLIP(short) and c-FLIP(R), the latter isoform is poorly characterized. We report here the characterization of murine c-FLIP(R) and show that it is the only short c-FLIP isoform expressed in mice. By generating several mutants, we demonstrate that both death effector domains (DEDs) are required for DISC binding and the antiapoptotic function of c-FLIP(R). Surprisingly, the C-terminal tail is important for both protein stability and DISC recruitment. Three-dimensional modeling of c-FLIP(R) revealed a substantial similarity of the overall structures and potential interaction motifs with the viral FLIP MC159. We found, however, that c-FLIP(R) uses different structural motifs for its DISC recruitment. Whereas MC159 interferes with interaction and self-oligomerization of the DISC component FADD by its extensive hydrophilic surface, a narrow hydrophobic patch of c-FLIP(R) on the surface of DED2 is crucial for DISC association. Thus, despite the presence of similar tandem DEDs, viral and cellular FLIPs inhibit apoptosis by remarkably divergent mechanisms. |
