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Nature. 2016 Dec 1;540(7631):129-133. doi: 10.1038/nature20559. Epub 2016 Nov 7.

RIPK1 inhibits ZBP1-driven necroptosis during development.

Author information

1
Department of Physiological Chemistry, Genentech, 1 DNA Way, South San Francisco, California 94080, USA.
2
Molecular Genetics of Cancer Division, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia.
3
Department of Medical Biology, Melbourne University, Victoria 3010, Australia.
4
Department of Proteomics and Biological Resources, Genentech, 1 DNA Way, South San Francisco, California 94080, USA.
5
Department of Molecular Biology, Genentech, 1 DNA Way, South San Francisco, California 94080, USA.
6
Department of Pathology, Genentech, 1 DNA Way, South San Francisco, California 94080, USA.

Abstract

Receptor-interacting protein kinase 1 (RIPK1) promotes cell survival-mice lacking RIPK1 die perinatally, exhibiting aberrant caspase-8-dependent apoptosis and mixed lineage kinase-like (MLKL)-dependent necroptosis. However, mice expressing catalytically inactive RIPK1 are viable, and an ill-defined pro-survival function for the RIPK1 scaffold has therefore been proposed. Here we show that the RIP homotypic interaction motif (RHIM) in RIPK1 prevents the RHIM-containing adaptor protein ZBP1 (Z-DNA binding protein 1; also known as DAI or DLM1) from activating RIPK3 upstream of MLKL. Ripk1RHIM/RHIM mice that expressed mutant RIPK1 with critical RHIM residues IQIG mutated to AAAA died around birth and exhibited RIPK3 autophosphorylation on Thr231 and Ser232, which is a hallmark of necroptosis, in the skin and thymus. Blocking necroptosis with catalytically inactive RIPK3(D161N), RHIM mutant RIPK3, RIPK3 deficiency, or MLKL deficiency prevented lethality in Ripk1RHIM/RHIM mice. Loss of ZBP1, which engages RIPK3 in response to certain viruses but previously had no defined role in development, also prevented perinatal lethality in Ripk1RHIM/RHIM mice. Consistent with the RHIM of RIPK1 functioning as a brake that prevents ZBP1 from engaging the RIPK3 RHIM, ZBP1 interacted with RIPK3 in Ripk1RHIM/RHIMMlkl-/- macrophages, but not in wild-type, Mlkl-/- or Ripk1RHIM/RHIMRipk3RHIM/RHIM macrophages. Collectively, these findings indicate that the RHIM of RIPK1 is critical for preventing ZBP1/RIPK3/MLKL-dependent necroptosis during development.

PMID:
27819682
DOI:
10.1038/nature20559
[Indexed for MEDLINE]

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