RIP1 suppresses innate immune necrotic as well as apoptotic cell death during mammalian parturition
Open accessAbstract
Significance: The protein kinase receptor interacting protein 1 controls signaling via death receptors, Toll-like receptors, and retinoic acid-inducible gene 1-like receptors, dictating inflammatory outcomes as broad as cytokine activation and cell death. RIP1 makes a vital contribution during development, evident from the fact that RIP1-deficient mice die soon after birth. Here, we show that a kinase-independent function of RIP1 dampens the consequences of innate immune cell death. During parturition, RIP1 prevents the lethal consequences of RIP3-dependent necroptosis as well as caspase 8 (Casp8)-dependent apoptosis. In contrast to the RIP1-deficient phenotype, mice lacking a combination of RIP1, RIP3, and Casp8 are born and mature into viable, fertile, and immunocompetent adults. These results demonstrate the important protective role of RIP1 against physiologic and microbial death cues encountered at birth.
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Ripk1−/− cells display increased sensitivity to necroptosis and/or extrinsic apoptosis induced by a set of innate immune stimuli.
“Moreover, Ripk1−/− cells display increased sensitivity to necroptosis and/or extrinsic apoptosis induced by a set of innate immune stimuli [499].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [499]
Pro-survival role of RIPK1 in development seems independent of both its kinase activity and RIPK3 binding, as mice expressing kinase-dead RIPK1 (e.g., RIPK1K45A) are viable and fertile.
“Intriguingly, the pro-survival role of RIPK1 in development seems to be independent of both its kinase activity and RIPK3 binding, as demonstrated by the fact that mice genetically engineered to express a kinase-dead variant of RIPK1 (e.g., RIPK1K45A) are viable and fertile [447, 499, 508].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [499]
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- Authors
- Kaiser, W. J., Daley-Bauer, L. P., Thapa, R. J., Mandal, P., Berger, S. B., Huang, C., Sundararajan, A., Guo, H., Roback, L., Speck, S. H., Bertin, J., Gough, P. J., Balachandran, S., & Mocarski, E. S.
- Affiliations
- Emory University (US)
- Department of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322;
- Fox Chase Cancer Center (US)
- GlaxoSmithKline (United States) (US)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2014-05-12
- Volume
- 111
- Issue
- 21
- Pages
- 7753-7758
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC4040608
- OpenAlex
- W2069250210
- Cited by
- 291
- References
- 41
- Citations by year
- 2026: 7 · 2025: 12 · 2024: 17 · 2023: 14 · 2022: 17 · 2021: 24 · 2020: 28 · 2019: 29 · 2018: 25 · 2017: 26 · 2016: 39 · 2015: 30 · 2014: 22
- FWCI
- 15.90
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (DP5OD012198)
- U.S. Public Health Service (R5630363)
- National Cancer Institute (R01CA168621, T32CA009035)
- National Institute of Allergy and Infectious Diseases (R01AI020211, R21AI104212, R01AI118853)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Keywords
- RIPK1, RIPK3, caspase-8, necroptosis, apoptosis, innate immunity, childbirth, perinatal lethality, kinase-independent function, TNF-α, interferon, double-stranded RNA, antiviral immunity
- MeSH terms
- Animals, Enzyme-Linked Immunosorbent Assay, Flow Cytometry, Immunity, Innate, Necrosis, Immunoblotting, Signal Transduction, Apoptosis, DNA Primers, Mice, Knockout, GTPase-Activating Proteins, Parturition, Mice, Caspase 8, Receptor-Interacting Protein Serine-Threonine Kinases, Gene Knock-In Techniques
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