RIPK1 inhibits ZBP1-driven necroptosis during development
Publication Year 2016, Volume 540, Issue #7631, Page 129-133
Journal Title
Publication Type
Journal Article
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.
Springer Nature
WEHI Research Division(s)
Molecular Genetics Of Cancer
PubMed ID
Rights Notice
Refer to copyright notice on published article.

Creation Date: 2016-11-14 11:36:25
Last Modified: 2018-07-04 03:14:01
An error has occurred. This application may no longer respond until reloaded. Reload 🗙