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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RIPK3 can be activated following RHIM-dependent interaction with ZBP1, which operates as sensor for cytosolic DNA-promoting type I IFN synthesis and NF-κB activation.
“or (2) ZBP1, which operates as a sensor for cytosolic DNA-promoting type I interferon (IFN) synthesis and NF-κB activation [439–441].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [441]
Mice expressing variant of RIPK1 mutated in RHIM domain die perinatally, a phenotype that can be rescued by concurrent Ripk3, Mlkl, or Zbp1 (but not Ticam1) deletion, as well as by knock-in of catalytically inactive RIPK3 or RIPK3 mutated in RHIM domain.
“Moreover, mice expressing a variant of RIPK1 mutated in the RHIM domain die perinatally, a phenotype that can be rescued by concurrent Ripk3, Mlkl, or Zbp1 (but not Ticam1) deletion, as well as by the knock-in of catalytically inactive RIPK3 or RIPK3 mutated in the RHIM domain [440, 441].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [441]
ZBP1 acts at initial steps of necroptosis by mediating sequential activation of RIPK3 and MLKL.
“ZBP1 acts at the initial steps of necroptosis by mediating the sequential activation of RIPK3 and MLKL.”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [441]
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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
- 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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