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

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RIPK1 inhibits ZBP1-driven necroptosis during development

Newton, Kim, Wickliffe, Katherine E., Maltzman, Allie, Dugger, Debra L., Strasser, Andreas, Pham, Victoria C., Lill, Jennie R., Roose-Girma, Merone, Warming, Søren, Solon, Margaret, Ngu, Hai, Webster, Joshua D., Dixit, Vishva M.·2016·Nature

DOI 10.1038/nature20559

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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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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.
ORCID: Newton, Kim
Dugger, Debra L.
Strasser, Andreas
Pham, Victoria C.
Lill, Jennie R.
Warming, Søren
Solon, Margaret
Ngu, Hai
Webster, Joshua D.
Dixit, Vishva M.
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2016-11-07
Volume: 540
Issue: 7631
Pages: 129-133
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/nature20559
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
Licence: www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
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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RIPK1 inhibits ZBP1-driven necroptosis during development

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