| First Author | Zhang X | Year | 2019 |
| Journal | Cell Death Dis | Volume | 10 |
| Issue | 3 | Pages | 245 |
| PubMed ID | 30867408 | Mgi Jnum | J:280188 |
| Mgi Id | MGI:6369186 | Doi | 10.1038/s41419-019-1490-8 |
| Citation | Zhang X, et al. (2019) RIPK1 can mediate apoptosis in addition to necroptosis during embryonic development. Cell Death Dis 10(3):245 |
| abstractText | RIPK1 has emerged as a key effector in programmed necrosis or necroptosis. This function of RIPK1 is mediated by its protein serine/threonine kinase activity and through the downstream kinase RIPK3. Deletion of RIPK1 prevents embryonic lethality in mice lacking FADD, a signaling adaptor protein required for activation of Caspase 8 in extrinsic apoptotic pathways. This indicates that FADD-mediated apoptosis inhibits RIPK1-dependent necroptosis to ensure successful embryogenesis. However, the molecular mechanism for this critical regulation remains unclear. In the current study, a novel mouse model has been generated, by disrupting a potential caspase cleavage site at aspartic residue (D)324 in RIPK1. Interestingly, replacing D324 with alanine (A) in RIPK1 results in midgestation lethality, similar to the embryonic defect in FADD(-/-) mice but in stark contrast to the normal embryogenesis of RIPK1(-/-) null mutant mice. Surprisingly, disrupting the downstream RIPK3 alone is insufficient to rescue RIPK1(D324A/D324A) mice from embryonic lethality, unless FADD is deleted simultaneously. Further analyses reveal a paradoxical role for RIPK1 in promoting caspase activation and apoptosis in embryos, a novel mechanism previously unappreciated. |
