Document Type

Article

Publication Date

3-1-2019

Comments

This article has been peer reviewed. It is the author’s final published version in Cell Death and Disease, Volume 10, Issue 3, March 2019, Article number 245.

The published version is available at https://doi.org/10.1038/s41419-019-1490-8. Copyright © Zhang et al.

Publication made possible in part by support from the Thomas Jefferson University + Philadelphia University Open Access Fund

Abstract

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. © 2019, The Author(s)

Creative Commons License

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.

PubMed ID

30867408

Language

English

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