RIPK1 inhibits ZBP1-driven necroptosis during development

Newton, K; Wickliffe, KE; Maltzman, A; Dugger, DL; Strasser, A; Pham, VC; Lill, JR; Roose-Girma, M; Warming, S; Solon, M; Ngu, H; Webster, JD; Dixit, VM

Author(s): Newton, K; Wickliffe, KE; Maltzman, A; Dugger, DL; Strasser, A; Pham, VC; Lill, JR; Roose-Girma, M; Warming, S; Solon, M; Ngu, H; Webster, JD; Dixit, VM;
Details: Publication Year 2016,Volume 540,Issue #7631,Page 129-133
Journal Title: Nature
Publication Type: Journal Article
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 necroptosis1,2,3. However, mice expressing catalytically inactive RIPK1 are viable2,4,5, so an ill-defined pro-survival function for the RIPK1 scaffold has 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 called DAI) from activating RIPK3 upstream of MLKL. Ripk1RHIM/RHIM mice expressing 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 necroptosis6, 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 viruses7,8 but previously had no role during 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/RHIM Mlkl-/- macrophages, but not in wild-type, Mlkl-/- or Ripk1RHIM/RHIM Ripk3RHIM/RHIM macrophages. Collectively, these findings indicate that the RHIM of RIPK1 is critical for preventing ZBP1/RIPK3/MLKL-dependent necroptosis during development.
Publisher: Springer Nature
Research Division(s): Molecular Genetics Of Cancer
PubMed ID: 27819682
Publisher's Version: https://doi.org/10.1038/nature20559
Terms of Use/Rights Notice: Refer to copyright notice on published article.
Documents: Newton K et al_Nature_2016.pdf - (2.60MB, application/pdf)

Creation Date: 2016-11-14 11:36:25

Last Modified: 2018-07-04 03:14:01