RIPK1 can mediate apoptosis in addition to necroptosis during embryonic development
Description
<jats:title>Abstract</jats:title><jats:p>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<jats:sup>−/−</jats:sup> mice but in stark contrast to the normal embryogenesis of RIPK1<jats:sup>−/−</jats:sup> null mutant mice. Surprisingly, disrupting the downstream RIPK3 alone is insufficient to rescue RIPK1<jats:sup>D324A/D324A</jats:sup> 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.</jats:p>
Journal
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- Cell Death & Disease
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Cell Death & Disease 10 (3), 245-, 2019-03-13
Springer Science and Business Media LLC
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Details 詳細情報について
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- CRID
- 1360576285425634944
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- ISSN
- 20414889
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- Data Source
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- Crossref