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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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“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]
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“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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BackgroundAbsence of RIPK3 predicts necroptosis resistance in malignant melanoma
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RIPK1 Suppresses a TRAF2-Dependent Pathway to Liver Cancer
Schneider, A. T., Gautheron, J., Feoktistova, M., Roderburg, C., Loosen, S. H., Roy, S., Benz, F., Schemmer, P., Büchler, M. W., Nachbur, U., et al. (2017) · Cancer Cell · doi:10.1016/j.ccell.2016.11.009 · Cited by 155
“Moreover, Casp8 deficiency did not rescue the perinatal lethality of Ripk1-full-knockout mice, but prevented apoptosis in many tissues including intestine, thymus, liver, and lung (Dillon et al., 2014; Kaiser et al., 2014).”
BackgroundNecroptosis, in vivo detection in experimental disease models
Jouan-Lanhouet, S., Riquet, F. B., Duprez, L., Berghe, T. V., Takahashi, N., & Vandenabeele, P. (2014) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2014.08.010 · Cited by 166
“Recently, Ripk1 kinase dead KI animals became available to the scientific community [14, 15], allowing the distinction between RIPK1 kinase-independent platform functions (NF-κB and MAPKs activation, cell survival), and the kinase-dependent ones.”
BackgroundInfluentialJacobsen, A. V., Lowes, K. N., Tanzer, M. C., Lucet, I. S., Hildebrand, J. M., Petrie, E. J., van Delft, M. F., Liu, Z., Conos, S. A., Zhang, J.-G., et al. (2016) · Cell Death & Disease · doi:10.1038/cddis.2015.386 · Cited by 160
“uninduced induced DM SO AT 13 38 7 NV P- BE P8 00 17 -A AG 0 20 40 60 80 100 MLKL(1-180) in Mlkl-/- MDFs”
BackgroundSchwarzer, R., Laurien, L., & Pasparakis, M. (2020) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2020.02.004 · Cited by 162
Günther, C., He, G.-W., Kremer, A. E., Murphy, J. M., Petrie, E. J., Amann, K., Vandenabeele, P., Linkermann, A., Poremba, C., Schleicher, U., et al. (2016) · Journal of Clinical Investigation · doi:10.1172/jci87545 · Cited by 157
RIP1/RIP3-regulated necroptosis as a target for multifaceted disease therapy (Review)
Liu, Y., Liu, T., Lei, T., Zhang, D., Du, S., Girani, L., Qi, D., Chen, L., Tong, R., & Wang, Y. (2019) · International Journal of Molecular Medicine · doi:10.3892/ijmm.2019.4244 · Cited by 157
“Nevertheless, a recent study revealed that RIP1-deficient mice die soon after birth, leading to speculation for the positive role of RIP1 in embryonic development and postnatal life (83).”
BackgroundStructure Guided Design of Potent and Selective Ponatinib-Based Hybrid Inhibitors for RIPK1
Najjar, M., Suebsuwong, C., Ray, S. S., Thapa, R. J., Maki, J. L., Nogusa, S., Shah, S., Saleh, D., Gough, P. J., Bertin, J., et al. (2015) · Cell Reports · doi:10.1016/j.celrep.2015.02.052 · Cited by 156
“We confirmed that activation of cell death in RIPK1−/− MEFs by IFNγ was dependent on RIPK3 by demonstrating blockade of cell death by the RIPK3 inhibitor GSK-872 (Fig.”
BackgroundInfluentialSelf-citationProgrammed necrosis and necroptosis signalling
Feoktistova, M., & Leverkus, M. (2014) · FEBS Journal · doi:10.1111/febs.13120 · Cited by 159
Cell death in chronic inflammation: breaking the cycle to treat rheumatic disease
Anderton, H., Wicks, I. P., & Silke, J. (2020) · Nature Reviews Rheumatology · doi:10.1038/s41584-020-0455-8 · Cited by 152
Suppression of RIP3-dependent Necroptosis by Human Cytomegalovirus
Omoto, S., Guo, H., Talekar, G. R., Roback, L., Kaiser, W. J., & Mocarski, E. S. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.646042 · Cited by 145
“For real-time imaging of cell permeability with IncuCyte Zoom (Essen Bioscience), cells (15,000 cells/well) were seeded into Corning 48-well tissue culture plates and cultured in medium containing 50 nM SYTOX Green (Molecular Probes) or 5 M propidium iodide (PI) (Sigma) (15).”
MethodSelf-citationRole of necroptosis in the pathogenesis of solid organ injury
Zhao, H., Jaffer, T., Eguchi, S., Wang, Z., Linkermann, A., & Ma, D. (2015) · Cell Death and Disease · doi:10.1038/cddis.2015.316 · Cited by 143
“The kinase domain of RIPK1 appears to be of central importance in sepsis/LPS/TNF-mediated shock models.(25,27) A range of chemical or biological compounds have been proposed or investigated as potential inhibitors of RIPK1 in organ injury.”
BackgroundNonapoptotic cell death in acute kidney injury and transplantation
Linkermann, A. (2016) · Kidney International · doi:10.1016/j.kint.2015.10.008 · Cited by 141
Cell death checkpoints in the TNF pathway
Huyghe, J., Priem, D., & Bertrand, M. J. M. (2023) · Trends in Immunology · doi:10.1016/j.it.2023.05.007 · Cited by 147
The Two Faces of Receptor Interacting Protein Kinase-1
Weinlich, R., & Green, D. R. (2014) · Molecular Cell · doi:10.1016/j.molcel.2014.11.001 · Cited by 132
Insights on the crosstalk among different cell death mechanisms
Eskander, G., AbdelHamid, S. G., Wahdan, S. A., & Radwan, S. M. (2025) · Cell Death Discovery · doi:10.1038/s41420-025-02328-9 · Cited by 150
“While mice lacking RIPK1, caspase-8, and RIPK3 were able to survive to adulthood [175 – 177].”
An outline of necrosome triggers
Berghe, T. V., Hassannia, B., & Vandenabeele, P. (2016) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-016-2189-y · Cited by 134
Caspase-8 Collaborates with Caspase-11 to Drive Tissue Damage and Execution of Endotoxic Shock
Mandal, P., Feng, Y., Lyons, J. D., Berger, S. B., Otani, S., DeLaney, A. A., Tharp, G. K., Maner-Smith, K. M., Burd, E. M., Schaeffer, M. C., et al. (2018) · Immunity · doi:10.1016/j.immuni.2018.06.011 · Cited by 131
“Given that Ripk1Casp8Ripk3 and Ripk1Casp8Ripk3 mice (Kaiser et al., 2014) both resisted LPS (Figure S1B), Casp8 function appeared to be independent of RIPK3.”
InfluentialSelf-citationHu, X., Li, Z., Lin, R., Shan, J.-Q., Yu, Q., Wang, R., Liao, L., Yan, W., Zhen, W., Shang, L., et al. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.634690 · Cited by 135
A long-awaited merger of the pathways mediating host defence and programmed cell death
Blander, J. M. (2014) · Nature reviews. Immunology · doi:10.1038/nri3720 · Cited by 127
Diverse ubiquitin linkages regulate RIP kinases-mediated inflammatory and cell death signaling
Witt, A., & Vucic, D. (2017) · Cell Death and Differentiation · doi:10.1038/cdd.2017.33 · Cited by 133
“Diverse necroptotic stimuli lead to the activation of cell death through the modulation of RIP1 and/or RIP3 kinase activity.(60,75,76) However, recent studies imply a more diverse picture of post-transcriptional modifications regulating the necrosome.”
BackgroundCaspase‐8: not so silently deadly
Feltham, R., Vince, J. E., & Lawlor, K. E. (2017) · Clinical & Translational Immunology · doi:10.1038/cti.2016.83 · Cited by 124
Sensing of endogenous nucleic acids by ZBP1 induces keratinocyte necroptosis and skin inflammation
Devos, M., Tanghe, G., Gilbert, B., Dierick, E., Verheirstraeten, M., Nemegeer, J., de Reuver, R., Lefebvre, S., Munck, J. D., Rehwinkel, J., et al. (2020) · The Journal of Experimental Medicine · doi:10.1084/jem.20191913 · Cited by 124
The regulation of necroptosis by post-translational modifications
Meng, Y., Sandow, J. J., Czabotar, P. E., & Murphy, J. M. (2021) · Cell Death and Differentiation · doi:10.1038/s41418-020-00722-7 · Cited by 130
A new kind of cell suicide: mechanisms and functions of programmed necrosis
Sun, L., & Wang, X. (2014) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2014.10.003 · Cited by 123
Li, X., Zhong, C., Wu, R., Xu, X., Yang, Z., Cai, S., Wu, X., Chen, X., Yin, Z., He, Q., et al. (2021) · Protein & Cell · doi:10.1007/s13238-020-00810-x · Cited by 117
Coordinated ubiquitination and phosphorylation of RIP1 regulates necroptotic cell death
de Almagro, M. C., Goncharov, T., Izrael-Tomasevic, A., Duttler, S., Kist, M., Varfolomeev, E. E., Wu, X., Lee, W. P., Murray, J. M., Webster, J. D., et al. (2016) · Cell Death and Differentiation · doi:10.1038/cdd.2016.78 · Cited by 125
“Diverse necroptotic stimuli converge on the activation of RIP1 and RIP3 kinases.(5,19,20) Thus, it is not surprising that necroptotic cell death signaling can be regulated through the modulation of RIP1 and RIP3 kinase activities.”
BackgroundMcComb, S., Aguadé-Gorgorió, J., Behrmann, L., Marovca, B., Cario, G., Eckert, C., Schrappe, M., Stanulla, M., von Stackelberg, A., Bourquin, J., et al. (2016) · Science Translational Medicine · doi:10.1126/scitranslmed.aad2986 · Cited by 118
Necroptosis: Pathway diversity and characteristics
de Almagro, M. C., & Vucic, D. (2015) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2015.02.002 · Cited by 118
Mosaic composition of RIP1–RIP3 signalling hub and its role in regulating cell death
Chen, X., Zhu, R., Zhong, J., Ying, Y., Wang, W., Cao, Y., Cai, H., Li, X., Shuai, J., & Han, J. (2022) · Nature Cell Biology · doi:10.1038/s41556-022-00854-7 · Cited by 114
RIPK1 can mediate apoptosis in addition to necroptosis during embryonic development
Zhang, X., Dowling, J. P., & Zhang, J. (2019) · Cell Death and Disease · doi:10.1038/s41419-019-1490-8 · Cited by 115
The in vivo evidence for regulated necrosis
Tonnus, W., & Linkermann, A. (2017) · Immunological Reviews · doi:10.1111/imr.12551 · Cited by 114
“DAI- ko Lethal, forces RIPK3 polymerization (56, 57) RIPK1K45A/D138N Kinase- dead RIPK1 Develop normally (52, 58) RIPK3K51A Kinase- dead RIPK3 Develop normally (59) RIPK3D161N Kinase- dead RIPK3 Lethal, seems to activate CASP- 8 in ripoptosome (52)”
BackgroundTanzer, M. C., Tripaydonis, A., Webb, A. I., Young, S. N., Varghese, L. N., Hall, C. M., Alexander, W. S., Hildebrand, J. M., Silke, J., & Murphy, J. M. (2015) · Biochemical Journal · doi:10.1042/bj20150678 · Cited by 116
Multitasking Kinase RIPK1 Regulates Cell Death and InflammationPreprint
Newton, K. (2019) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a036368 · Cited by 107
“The enzymatic activity of RIPK1 is dispensable for the prosurvival function of RIPK1 because mice expressing catalytically inactive RIPK1 are viable (Kaiser et al. 2014; Newton et al. 2014; Polykratis et al. 2014).”
BackgroundInfluentialRIPK3 promotes kidney fibrosis via AKT-dependent ATP citrate lyase
Imamura, M., Moon, J., Chung, K., Nakahira, K., Muthukumar, T., Shingarev, R. A., Ryter, S. W., Choi, A. M. K., & Choi, M. E. (2018) · JCI Insight · doi:10.1172/jci.insight.94979 · Cited by 108
“For chemical inhibition of RIPK3 or RIPK1, cells were treated with 10 μM GSK’872 (Calbiochem) or 60 μM Nec-1 for 1 hour and then treated with TGF-β1 (5 ng/ml) for 24 hours.”
ResultResearch trends, hot spots and prospects for necroptosis in the field of neuroscience
Xiong, K., Yan, W., Lu, S., Yang, Y., Ning, W.-Y., Cai, Y., Hu, X.-M., & Zhāng, Q. (2021) · Neural Regeneration Research · doi:10.4103/1673-5374.303032 · Cited by 107
“Furthermore, Degterev et al. (2005) found that Nec-1 can (Dillon et al., 2014; Kaiser et al., 2014; Rickard et al., 2014).”
Metadata
- 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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