RIP1 kinase activity-dependent roles in embryonic development of Fadd-deficient mice
Open accessAbstract
RIP1 is an essential regulator of TNF-induced signaling complexes mediating NF-κB activation, apoptosis and necroptosis. Loss of Rip1 rescues the embryonic lethality of Fadd or Caspase-8-deficient mice, even though the double knockout mice die shortly after birth like Rip1-deficient mice. Recent studies demonstrated that mice expressing RIP1 kinase-dead mutants developed normally and resisted necroptotic stimuli in vitro and in vivo. However, the impact of RIP1 kinase activity on Fadd-/- embryonic development remains unknown. Here, we engineered two RIP1 kinase inactive mutant mouse lines, a Rip1 K45A/K45A mouse line as previously reported and a novel Rip1 Δ/Δ mouse line with an altered P-loop in the kinase domain. While RIP1 K45A could not rescue the embryonic lethality of Fadd-deficient mice at E11.5, RIP1 Δ rescued lethality of Fadd-/- mice at E11.5 and Fadd-/-Rip1 Δ/Δ mice eventually died at E16.5 due to excessive death of fetal liver cells and unregulated inflammation. Under necropotosis-inducing conditions, comparing to Rip1 K45A/K45A cells, Rip1 Δ/Δ cells displayed reduced phosphorylation and oligomerization of RIP3 and MLKL, which lead to increased cell viability. Thus, our study provides genetic evidence that different kinase inactive mutations have distinct impacts on the embryogenesis of Fadd-deficient mice, which might attribute to their extents of protection on necroptosis signaling.
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Embryonic lethality imposed on mice by loss of Casp8 or Fadd can be rescued by concurrent ablation of Ripk3 or Mlkl, even though double knockout animals generally display lymphoproliferative and/or systemic autoimmune disorders as adults.
“Thus, the embryonic lethality imposed on mice by the loss of Casp8 or Fadd can be rescued by concurrent ablation of Ripk3 or Mlkl, even though these double knockout animals generally display lymphoproliferative and/or systemic autoimmune disorders as adults [432, 466, 484, 485].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [485]
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“…early signaling stage before TNF treatment is also indispensable for necroptosis induction because suppression of RIPK1 and RIPK3 spontaneous phosphorylation through kinase-dead mutation blocks necrosome formation and necroptosis (Vandenabeele et al., 2010; Kaiser et al., 2014; Liu et al., 2017).”
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“Knock-out (KO) of RIP1 in mice leads to perinatal lethality with increased systemic inflammation and cell death.(15,16,20)”
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Self-citationKW2449 ameliorates collagen-induced arthritis by inhibiting RIPK1-dependent necroptosis
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“In previous experiments, RIPK1 deletion caused the death of rats shortly after birth, and the RIPK1 skeleton was assumed to play a protective role (36, 37).”
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“In contrast, RIPK1KD/KD D138N and RIPK1 P-loop deficient RIP1∆/∆ mice were not protected from CER-AP [12,14].”
BackgroundResultRIPK1-Associated Inborn Errors of Innate Immunity
Zhang, J., Jin, T., Aksentijevich, I. A., & Zhou, Q. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.676946 · Cited by 22 · see citing works
“In contrast to the phenotype of constitutive and conditional Ripk1–/– mice, mice engineered with RIPK1 knock-in (KI) kinase-dead mutations, including Asp138Asn (43), Lys45Ala (5, 44), Gly27_Phe28del (45) and the Lys584Arg (46) mutation affecting the dimerization of death domain, are viable and normal, which indicates…”
BackgroundSPOP promotes FADD degradation and inhibits NF-κB activity in non-small cell lung cancer
Luo, J., Chen, B., Gao, C., Xie, H., Han, C., & Zhou, C. (2018) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2018.08.176 · Cited by 21 · see citing works
Hua, Y., Qian, J., Cao, J., Wang, X. B., Zhang, W., & Zhang, J. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23136988 · Cited by 17 · see citing works
“Necroptosis is closely related to embryonic development [17], inflammation [18], neurodegeneration [19], tumors [20], cardiovascular disease [21], and other physiological and pathological processes.”
BackgroundLi, M., Liu, Y., Xu, C., Zhao, Q., Liu, J., Xing, M., Li, X., Zhang, H., Wu, X., Wang, L., et al. (2022) · Cell Death and Differentiation · doi:10.1038/s41418-022-00994-1 · Cited by 17 · see citing works
Self-citationYang, Y., He, X., Xia, S., Liu, F., & Luo, L. (2020) · Journal of Periodontal Research · doi:10.1111/jre.12812 · Cited by 16 · see citing works
Kang, K., Lee, S., Piao, X., & Hur, G. M. (2019) · Archives of Pharmacal Research · doi:10.1007/s12272-018-01107-8 · Cited by 15 · see citing works
Z-DNA-binding protein 1-mediated programmed cell death: Mechanisms and therapeutic implications
Huang, Y., Wang, L., Zhu, Y., Li, X., Dai, Y., He, G., & Jiang, X. F. (2025) · Chinese Medical Journal · doi:10.1097/cm9.0000000000003737 · Cited by 14 · see citing works
“Stimuli that can induce necrop-tosis include death receptor, [60] which is a subset of the tumor necrosis factor receptor (TNFR) family, Toll-like receptors (TLRs), especially TLR3 and TLR4, [61] IFNs, [62] and the intracellular viral sensor ZBP1.”
Self-citationThe interaction between RIPK1 and FADD controls perinatal lethality and inflammation
Rodríguez, D. A., Tummers, B., Shaw, J. J. P., Quarato, G., Weinlich, R., Cripps, J. G., Fitzgerald, P., Janke, L. J., Pelletier, S. W., Crawford, J. C., et al. (2024) · Cell Reports · doi:10.1016/j.celrep.2024.114335 · Cited by 14 · see citing works
“Since the interaction of RIPK1 with FADD is critical for Caspase-8 activation and cleavage-mediated disruption of RIPK1 activity, 40–42 and since the K45A mutation does not prevent embryonic lethality in Fadd −/− mice, 43 we predicted that both RIPK1 variants would be lethal.”
BackgroundRegulation of RIP1‐Mediated necroptosis via necrostatin‐1 in periodontitis
Tan, L., Chan, W., Zhang, J., Wang, J., Wang, Z., Liu, J., Li, J., Liu, X., Wang, M., Hao, L., et al. (2023) · Journal of Periodontal Research · doi:10.1111/jre.13150 · Cited by 13 · see citing works
METTL3 restricts RIPK1-dependent cell death via the ATF3-cFLIP axis in the intestinal epithelium
Huang, M., Wang, X., Zhang, M., Liu, Y., & Chen, Y. (2024) · Cell Regeneration · doi:10.1186/s13619-024-00197-8 · Cited by 10 · see citing works
“S5B) (Liu et al. 2017).”
Self-citationThe Encyclopedia of Proteome Dynamics: the KinoViewer
Brenes, A. J., & Lamond, A. I. (2018) · Bioinformatics · doi:10.1093/bioinformatics/bty823 · Cited by 9 · see citing works
“…are key elements within signal transduction pathways and studying their expression and mode of action can be critical for characterizing mechanisms regulating such processes as development (Liu et al., 2017), renewal (Annerén et al., 2004; Kinehara et al., 2013) and disease (Lahiry et al., 2010).”
BackgroundPiao, X., Byun, H. S., Lee, S., Ju, E., Park, K. A., Sohn, K., Quan, K. T., Lee, J., Na, M., & Hur, G. M. (2021) · Biochemical Pharmacology · doi:10.1016/j.bcp.2021.114733 · Cited by 11 · see citing works
Zhang, H., Wu, X., Li, M., Li, X., Wang, L., Liu, J., Ou, Y., Wu, X., Xing, M., Li, F., et al. (2022) · ImmunoHorizons · doi:10.4049/immunohorizons.2200021 · Cited by 6 · see citing works
Self-citationEvidence for the involvement of caspases in establishing proper cerebrospinal fluid hydrodynamics
Yoshida, A., Kawata, D., Shinotsuka, N., Yoshida, M., Yamaguchi, Y., & Miura, M. (2021) · Neuroscience Research · doi:10.1016/j.neures.2020.12.006 · Cited by 1 · see citing works
RIPK1 as a potential target to augment DC efficacy in tumor immunotherapy
Mao, L. F., Ou, Y., Zhang, Y., Wang, M., Dong, G., Khanniche, A., Wang, H., Wu, Z., Zhang, H., Hu, L. Y., et al. (2026) · Cancer Immunology Immunotherapy · doi:10.1007/s00262-026-04356-5
“Distinct from previous systemic RIPK1 modulation studies [25, 52, 53], we innovatively observed that DC-specific knockout of Ripk1 can remodel the tumor immune microenvironment and significantly augment DC vaccine efficacy.”
Self-citationResearch progress in PANoptosis mechanisms and their interplay with tuberculosis
Ma, X., Liang, Y., Wu, X., & An, H. (2026) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2026.1786786
Self-citation
- Authors
- Liu, Y., Fan, C., Zhang, Y., Yu, X., Wu, X., Zhang, X., Zhao, Q., Zhang, H., Xie, Q., Li, M., Li, X., Ding, Q., Ying, H., Li, D., & Zhang, H.
- Affiliations
- Chinese Academy of Sciences (CN)
- Shanghai Jiao Tong University (CN)
- Hubei University of Medicine (CN)
- Second Military Medical University (CN)
- East China Normal University (CN)
- Corresponding author
- Zhang, Haiwei
- Zhang, Haibing
- ORCID
- Venue
- Cell Death & Differentiation
- Published
- 2017-06-02
- Volume
- 24
- Issue
- 8
- Pages
- 1459-1469
- ISSN
- 1350-9047 (ISSN-L)
- 1476-5403
- PMC
- PMC5520462
- OpenAlex
- W2620640182
- Cited by
- 42
- References
- 51
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 4 · 2023: 3 · 2022: 6 · 2021: 9 · 2020: 3 · 2019: 7 · 2018: 7
- FWCI
- 1.90
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Cell Death and Differentiation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Thomas Jefferson University
- National Natural Science Foundation of China (31571426, 2016YFA0500100)
- Ministry of Science and Technology of the People's Republic of China (2016YFC1304900, 2016YFA0500100)
- Directorate for Biological Sciences
- David Geffen School of Medicine, University of California, Los Angeles
- 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 › Immune Response and Inflammation
- Keywords
- embryonic lethality, necroptosis, MLKL, kinase-dead mutant, P-loop mutations, uncontrolled inflammation, TNF signaling, apoptosis, embryonic development
- MeSH terms
- Animals, Embryo, Mammalian, Female, Genes, Lethal, Mutation, Phosphorylation, Pregnancy, Signal Transduction, Mice, Knockout, Gene Expression Regulation, Developmental, GTPase-Activating Proteins, Embryonic Development, Mice, Fas-Associated Death Domain Protein, Receptor-Interacting Protein Serine-Threonine Kinases, Protein Multimerization
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