Journal
NATURE
Volume 577, Issue 7788, Pages 103-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41586-019-1828-5
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Funding
- Intramural Research Programs of the National Human Genome Research Institute
- Intramural Research Program of NIH
- NIH Clinical Center
- National Institute of Arthritis and Musculoskeletal and Skin Diseases
- National Institute of Allergy and Infectious Diseases
- National Heart, Lung, and Blood Institute
- European Research Council [787826]
- NHMRC [1025594, 1046984, 1145788, 1162765, 1163581, 1081421, 1107149]
- Stafford Fox Foundation
- Australian Government NHMRC IRIISS [9000433]
- Australian Cancer Research Fund
- Cancer Australia [1145588]
- Cure Cancer Australia Foundation [1145588]
- Victorian Cancer Agency Mid-career Fellowship [17030]
- Australian Phenomics Network (APN)
- Australian Government through the National Collaborative Research Infrastructure Strategy (NCRIS) program
- NATIONAL HUMAN GENOME RESEARCH INSTITUTE [ZIAHG200372, ZIBHG000196, ZIAHG200373] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [ZIAAI000717, ZIAAI001122] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES [ZICAR041207, ZICAR041181] Funding Source: NIH RePORTER
- National Health and Medical Research Council of Australia [1107149, 1145788, 9000433, 1162765, 1163581, 1081421] Funding Source: NHMRC
- European Research Council (ERC) [787826] Funding Source: European Research Council (ERC)
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RIPK1 is a key regulator of innate immune signalling pathways. To ensure an optimal inflammatory response, RIPK1 is regulated post-translationally by well-characterized ubiquitylation and phosphorylation events, as well as by caspase-8-mediated cleavage1-7. The physiological relevance of this cleavage event remains unclear, although it is thought to inhibit activation of RIPK3 and necroptosis8. Here we show that the heterozygous missense mutations D324N, D324H and D324Y prevent caspase cleavage of RIPK1 in humans and result in an early-onset periodic fever syndrome and severe intermittent lymphadenopathy-a condition we term 'cleavage-resistant RIPK1-induced autoinflammatory syndrome'. To define the mechanism for this disease, we generated a cleavage-resistant Ripk1(D325A) mutant mouse strain. Whereas Ripk1(-/-) mice died postnatally from systemic inflammation, Ripk1(D325A/D325A) mice died during embryogenesis. Embryonic lethality was completely prevented by the combined loss of Casp8 and Ripk3, but not by loss of Ripk3 or Mlkl alone. Loss of RIPK1 kinase activity also prevented Ripk1(D325A/D325A) embryonic lethality, although the mice died before weaning from multi-organ inflammation in a RIPK3-dependent manner. Consistently, Ripk1(D325A/D325A) and Ripk1(D325A/+) cells were hypersensitive to RIPK3-dependent TNF-induced apoptosis and necroptosis. Heterozygous Ripk1(D325A/+) mice were viable and grossly normal, but were hyper-responsive to inflammatory stimuli in vivo. Our results demonstrate the importance of caspase-mediated RIPK1 cleavage during embryonic development and show that caspase cleavage of RIPK1 not only inhibits necroptosis but also maintains inflammatory homeostasis throughout life.
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