Cited by 390Cell death mechanisms and regulationNF-κB Signaling Pathwaysinterferon and immune responses

The DOI matches its Crossref record; 32 of the 32 references it cites were found in a registry or an index.

RIPK1 inhibits ZBP1-driven necroptosis during development

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. Ripk1 RHIM/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 Ripk1 RHIM/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 Ripk1 RHIM/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 Ripk1 RHIM/RHIM Mlkl-/- macrophages, but not in wild-type, Mlkl-/- or Ripk1 RHIM/RHIM Ripk3 RHIM/RHIM macrophages. Collectively, these findings indicate that the RHIM of RIPK1 is critical for preventing ZBP1/RIPK3/MLKL-dependent necroptosis during development.

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Crossref · 10.1038/nature20559

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Metadata

Authors
Newton, K., Wickliffe, K. E., Maltzman, A., Dugger, D. L., Strasser, A., Pham, V. C., Lill, J. R., Roose-Girma, M., Warming, S., Solon, M., Ngu, H., Webster, J. D., & Dixit, V. M.
Affiliations
  • Genentech (US)
  • The University of Melbourne (AU)
Corresponding author
  • Newton, Kim
  • Dixit, Vishva M.
Venue
Nature
Published
2016-11-07
Volume
540
Issue
7631
Pages
129-133
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
OpenAlex
W2547118804
Cited by
390
References
32
Citations by year
2026: 29 · 2025: 47 · 2024: 42 · 2023: 37 · 2022: 42 · 2021: 49 · 2020: 52 · 2019: 36 · 2018: 38 · 2017: 17 · 2016: 1
FWCI
15.85
Type
journal article
Language
en
Open access
closed
Locations
  • Nature (publishedVersion)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
Funders
Genentech
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
  • Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
Keywords
RIPK1, ZBP1, necroptosis, RIPK3, MLKL, RHIM domain, perinatal lethality, developmental cell death, innate immunity, thymus, DAI
MeSH terms
Animals, Animals, Newborn, Embryo, Mammalian, Female, Glycoproteins, Macrophages, Male, Mutation, Necrosis, Phosphorylation, Protein Binding, Protein Kinases, Tumor Necrosis Factor-alpha, RNA-Binding Proteins, Apoptosis, Amino Acid Motifs, Adaptor Proteins, Vesicular Transport, Mice, Caspase 8, Receptor-Interacting Protein Serine-Threonine Kinases

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