Journal article
Mutations that prevent caspase cleavage of RIPK1 cause autoinflammatory disease
N Lalaoui, SE Boyden, H Oda, GM Wood, DL Stone, D Chau, L Liu, M Stoffels, T Kratina, KE Lawlor, KJM Zaal, PM Hoffmann, N Etemadi, K Shield-Artin, C Biben, WL Tsai, MD Blake, HS Kuehn, D Yang, H Anderton Show all
Nature | Published : 2020
Abstract
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 def..
View full abstractGrants
Awarded by National Institute of Diabetes and Digestive and Kidney Diseases
Funding Acknowledgements
This study was funded by the Intramural Research Programs of the National Human Genome Research Institute, the Intramural Research Program of NIH, NIH Clinical Center, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institute of Allergy and Infectious Diseases, and National Heart, Lung, and Blood Institute, by European Research Council Advanced Grant 787826, by NHMRC grants 1025594, 1046984, 1145788, 1162765 and 1163581, NHMRC fellowships 1081421 and 1107149, by the Stafford Fox Foundation and was made possible through Victorian State Government Operational Infrastructure Support, Australian Government NHMRC IRIISS (9000433) and Australian Cancer Research Fund. N.L. is supported by project grant 1145588 from the Cancer Australia and Cure Cancer Australia Foundation and a Victorian Cancer Agency Mid-career Fellowship 17030. This work used the sequencing resources at the NIH Intramural Sequencing Center and the computational resources of the Biowulf Linux cluster at NIH (http://biowulf.nih.gov). We thank the families for their participation, D. Follmann for statistical advice, T. Uldrick and D. Fajgenbaum for assistance procuring samples, and D. Adams, A. Negro, A. Walts and Y. Yang for clinical and technical assistance, C. Liegeois for IT assistance and the staff of the WEHI Bioservices facility for mouse husbandry. The generation of Ripk1<SUP>D325</SUP>A and Ripk1<SUP>D138N,D325A</SUP> mice used in this study was supported by the Australian Phenomics Network (APN) and the Australian Government through the National Collaborative Research Infrastructure Strategy (NCRIS) program.