Mutations that prevent caspase cleavage of RIPK1 cause autoinflammatory disease,Nature

当前位置： X-MOL 学术 › Nature › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Mutations that prevent caspase cleavage of RIPK1 cause autoinflammatory disease
Nature ( IF 50.5 ) Pub Date : 2019-12-11 , DOI: 10.1038/s41586-019-1828-5
Najoua Lalaoui _{1,

2} , Steven E Boyden ₃ , Hirotsugu Oda ₃ , Geryl M Wood ₃ , Deborah L Stone ₃ , Diep Chau ₁ , Lin Liu _{1,

2} , Monique Stoffels ₃ , Tobias Kratina ₁ , Kate E Lawlor _{4,

5} , Kristien J M Zaal ₆ , Patrycja M Hoffmann ₃ , Nima Etemadi _{1,

2} , Kristy Shield-Artin _{1,

2} , Christine Biben _{1,

2} , Wanxia Li Tsai ₇ , Mary D Blake ₇ , Hye Sun Kuehn ₈ , Dan Yang ₉ , Holly Anderton _{1,

2} , Natasha Silke ₁ , Laurens Wachsmuth _{10,

11} , Lixin Zheng ₁₂ , Natalia Sampaio Moura ₃ , David B Beck ₃ , Gustavo Gutierrez-Cruz ₁₃ , Amanda K Ombrello ₃ , Gineth P Pinto-Patarroyo ₃ , Andrew J Kueh _{1,

2} , Marco J Herold _{1,

2} , Cathrine Hall ₁ , Hongying Wang ₃ , Jae Jin Chae ₃ , Natalia I Dmitrieva ₉ , Mark McKenzie _{1,

2} , Amanda Light ₁ , Beverly K Barham ₃ , Anne Jones ₃ , Tina M Romeo ₃ , Qing Zhou ₃ , Ivona Aksentijevich ₃ , James C Mullikin ₁₄ , Andrew J Gross ₁₅ , Anthony K Shum ₁₆ , Edwin D Hawkins _{1,

2} , Seth L Masters _{1,

2} , Michael J Lenardo ₁₂ , Manfred Boehm ₉ , Sergio D Rosenzweig ₈ , Manolis Pasparakis _{10,

11} , Anne K Voss _{1,

2} , Massimo Gadina ₇ , Daniel L Kastner ₃ , John Silke _{1,

2}

Affiliation

The Walter and Eliza Hall Institute, Parkville, Victoria, Australia.
Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
Inflammatory Disease Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia.
Department of Molecular and Translational Science, Monash University, Clayton, Victoria, Australia.
Light Imaging Section, Office of Science and Technology, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA.
Translational Immunology Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA.
Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, MD, USA.
Translational Vascular Medicine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
Institute for Genetics & Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
Center for Molecular Medicine (CMMC), University of Cologne, Cologne, Germany.
Molecular Development of the Immune System Section, Laboratory of Immune System Biology; Clinical Genomics Program, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
Laboratory of Muscle Stem Cells and Gene Regulation, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA.
NIH Intramural Sequencing Center, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
Division of Rheumatology, Department of Medicine, University of California San Francisco, San Francisco, CA, USA.
Division of Pulmonary and Critical Care, Department of Medicine, University of California San Francisco, San Francisco, CA, USA.

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 1 – 7 . The physiological relevance of this cleavage event remains unclear, although it is thought to inhibit activation of RIPK3 and necroptosis 8 . 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. Heterozygous mutateons in the caspase-8 cleavage site of RIPK1 cause a range of autoinflammatory symptoms in humans, and caspase-8 cleavage of RIPK1 in a mouse model limits TNF-induced cell death and inflammation.

中文翻译：

阻止 RIPK1 的半胱天冬酶切割的突变导致自身炎症性疾病

RIPK1 是先天免疫信号通路的关键调节因子。为了确保最佳的炎症反应，RIPK1 在翻译后受到充分表征的泛素化和磷酸化事件以及 caspase-8 介导的切割 1-7 的调节。这种分裂事件的生理相关性仍不清楚，尽管它被认为可以抑制 RIPK3 的激活和坏死性凋亡 8。在这里，我们显示杂合错义突变 D324N、D324H 和 D324Y 阻止了人类中 RIPK1 的半胱天冬酶裂解，并导致早发性周期性发热综合征和严重的间歇性淋巴结病——我们将这种情况称为“抗裂解 RIPK1 诱导的自身炎症综合征”。为了确定这种疾病的机制，我们产生了一种抗切割的 Ripk1 D325A 突变小鼠品系。Ripk1 -/- 小鼠在出生后死于全身炎症，而 Ripk1 D325A/D325A 小鼠在胚胎发生期间死亡。Casp8 和 Ripk3 的联合丢失完全防止了胚胎致死性，但仅通过丢失 Ripk3 或 Mlk1 并不能完全防止胚胎致死。RIPK1 激酶活性的丧失也阻止了 Ripk1 D325A/D325A 胚胎致死率，尽管小鼠在以 RIPK3 依赖性方式从多器官炎症断奶前死亡。一致地，Ripk1 D325A/D325A 和 Ripk1 D325A /+ 细胞对 RIPK3 依赖性 TNF 诱导的细胞凋亡和坏死性凋亡高度敏感。杂合的 Ripk1 D325A /+ 小鼠存活且基本正常，但对体内的炎症刺激反应过度。我们的研究结果证明了 caspase 介导的 RIPK1 切割在胚胎发育过程中的重要性，并表明 RIPK1 的 caspase 切割不仅抑制坏死性凋亡，而且在整个生命过程中维持炎症稳态。RIPK1 的 caspase-8 切割位点中的杂合突变会导致人类出现一系列自身炎症症状，并且小鼠模型中 RIPK1 的 caspase-8 切割限制了 TNF 诱导的细胞死亡和炎症。

更新日期：2019-12-11

点击分享查看原文

点击收藏

公开下载

阅读更多本刊新发论文本刊介绍/投稿指南