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Mutations that prevent caspase cleavage of RIPK1 cause autoinflammatory disease.

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 define the mechanism for this disease, we generated a cleavage-resistant Ripk1D325A mutant mouse strain. Whereas Ripk1-/- mice died postnatally from systemic inflammation, Ripk1D325A/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 Ripk1D325A/D325A embryonic lethality, although the mice died before weaning from multi-organ inflammation in a RIPK3-dependent manner. Consistently, Ripk1D325A/D325A and Ripk1D325A/+ cells were hypersensitive to RIPK3-dependent TNF-induced apoptosis and necroptosis. Heterozygous Ripk1D325A/+ 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.

SUBMITTER: Lalaoui N

PROVIDER: S-EPMC6930849 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Mutations that prevent caspase cleavage of RIPK1 cause autoinflammatory disease.

Lalaoui Najoua N Boyden Steven E SE Oda Hirotsugu H Wood Geryl M GM Stone Deborah L DL Chau Diep D Liu Lin L Stoffels Monique M Kratina Tobias T Lawlor Kate E KE Zaal Kristien J M KJM Hoffmann Patrycja M PM Etemadi Nima N Shield-Artin Kristy K Biben Christine C Tsai Wanxia Li WL Blake Mary D MD Kuehn Hye Sun HS Yang Dan D Anderton Holly H Silke Natasha N Wachsmuth Laurens L Zheng Lixin L Moura Natalia Sampaio NS Beck David B DB Gutierrez-Cruz Gustavo G Ombrello Amanda K AK Pinto-Patarroyo Gineth P GP Kueh Andrew J AJ Herold Marco J MJ Hall Cathrine C Wang Hongying H Chae Jae Jin JJ Dmitrieva Natalia I NI McKenzie Mark M Light Amanda A Barham Beverly K BK Jones Anne A Romeo Tina M TM Zhou Qing Q Aksentijevich Ivona I Mullikin James C JC Gross Andrew J AJ Shum Anthony K AK Hawkins Edwin D ED Masters Seth L SL Lenardo Michael J MJ Boehm Manfred M Rosenzweig Sergio D SD Pasparakis Manolis M Voss Anne K AK Gadina Massimo M Kastner Daniel L DL Silke John J

Nature 20191211 7788

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 cleavage<sup>1-7</sup>. The physiological relevance of this cleavage event remains unclear, although it is thought to inhibit activation of RIPK3 and necroptosis<sup>8</sup>. Here we show that the heterozygous missense mutations D324N, D324H and D324Y pre ...[more]

PMID: 31827281

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Project description:BackgroundAdult-onset inflammatory syndromes often manifest with overlapping clinical features. Variants in ubiquitin-related genes, previously implicated in autoinflammatory disease, may define new disorders.MethodsWe analyzed peripheral-blood exome sequence data independent of clinical phenotype and inheritance pattern to identify deleterious mutations in ubiquitin-related genes. Sanger sequencing, immunoblotting, immunohistochemical testing, flow cytometry, and transcriptome and cytokine profiling were performed. CRISPR-Cas9-edited zebrafish were used as an in vivo model to assess gene function.ResultsWe identified 25 men with somatic mutations affecting methionine-41 (p.Met41) in UBA1, the major E1 enzyme that initiates ubiquitylation. (The gene UBA1 lies on the X chromosome.) In such patients, an often fatal, treatment-refractory inflammatory syndrome develops in late adulthood, with fevers, cytopenias, characteristic vacuoles in myeloid and erythroid precursor cells, dysplastic bone marrow, neutrophilic cutaneous and pulmonary inflammation, chondritis, and vasculitis. Most of these 25 patients met clinical criteria for an inflammatory syndrome (relapsing polychondritis, Sweet's syndrome, polyarteritis nodosa, or giant-cell arteritis) or a hematologic condition (myelodysplastic syndrome or multiple myeloma) or both. Mutations were found in more than half the hematopoietic stem cells, including peripheral-blood myeloid cells but not lymphocytes or fibroblasts. Mutations affecting p.Met41 resulted in loss of the canonical cytoplasmic isoform of UBA1 and in expression of a novel, catalytically impaired isoform initiated at p.Met67. Mutant peripheral-blood cells showed decreased ubiquitylation and activated innate immune pathways. Knockout of the cytoplasmic UBA1 isoform homologue in zebrafish caused systemic inflammation.ConclusionsUsing a genotype-driven approach, we identified a disorder that connects seemingly unrelated adult-onset inflammatory syndromes. We named this disorder the VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome. (Funded by the NIH Intramural Research Programs and the EU Horizon 2020 Research and Innovation Program.).

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Mutations that prevent caspase cleavage of RIPK1 cause autoinflammatory disease.

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Mutations that prevent caspase cleavage of RIPK1 cause autoinflammatory disease.

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