A dominant autoinflammatory disease caused by non-cleavable variants of RIPK1

Nature. 2020 Jan;577(7788):109-114. doi: 10.1038/s41586-019-1830-y.

Panfeng Tao ^# ¹, Jinqiao Sun ^# ², Zheming Wu ^# ³, Shihao Wang ^# ¹, Jun Wang ^# ¹, Wanjin Li ^# ⁴, Heling Pan ³, Renkui Bai ⁵, Jiahui Zhang ¹, Ying Wang ², Pui Y Lee ⁶, Wenjing Ying ², Qinhua Zhou ², Jia Hou ², Wenjie Wang ², Bijun Sun ², Mi Yang ², Danru Liu ², Ran Fang ¹, Huan Han ¹, Zhaohui Yang ¹, Xin Huang ³, Haibo Li ⁷, Natalie Deuitch ⁸, Yuan Zhang ⁹, Dilan Dissanayake ¹⁰, Katrina Haude ⁵, Kirsty McWalter ⁵, Chelsea Roadhouse ¹¹, Jennifer J MacKenzie ¹¹ ¹², Ronald M Laxer ¹³, Ivona Aksentijevich ¹⁴, Xiaomin Yu ¹⁵, Xiaochuan Wang ¹⁶, Junying Yuan ¹⁷, Qing Zhou ¹⁸ ¹⁹

Affiliations

1 The MOE Key Laboratory of Biosystems Homeostasis & Protection, Life Sciences Institute, Zhejiang University, Hangzhou, China.
2 Department of Clinical Immunology, Children's Hospital of Fudan University, Shanghai, China.
3 Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China.
4 Department of Cell Biology, Harvard Medical School, Boston, MA, USA.
5 GeneDx, Gaithersburg, MD, USA.
6 Division of Immunology, Boston Children's Hospital, Boston, MA, USA.
7 Ningbo Women and Children's Hospital, Ningbo, China.
8 Department of Human Genetics, Stanford University School of Medicine, Stanford, CA, USA.
9 Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
10 Division of Rheumatology, Department of Paediatrics, The Hospital for Sick Children and the University of Toronto, Toronto, Ontario, Canada.
11 Department of Pediatrics, McMaster Children's Hospital, Hamilton, Ontario, Canada.
12 McMaster University, Hamilton, Ontario, Canada.
13 Division of Rheumatology, Departments of Paediatrics and Medicine, The Hospital for Sick Children and the University of Toronto, Toronto, Ontario, Canada.
14 Inflammatory Disease Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
15 The MOE Key Laboratory of Biosystems Homeostasis & Protection, Life Sciences Institute, Zhejiang University, Hangzhou, China. [email protected].
16 Department of Clinical Immunology, Children's Hospital of Fudan University, Shanghai, China. [email protected].
17 Department of Cell Biology, Harvard Medical School, Boston, MA, USA. [email protected].
18 The MOE Key Laboratory of Biosystems Homeostasis & Protection, Life Sciences Institute, Zhejiang University, Hangzhou, China. [email protected].
19 Women's Hospital, Zhejiang University School of Medicine, Hangzhou, China. [email protected].
# Contributed equally.

PMID: 31827280 DOI: 10.1038/s41586-019-1830-y

Abstract

Activation of RIPK1 controls TNF-mediated Apoptosis, Necroptosis and inflammatory pathways¹. Cleavage of human and mouse RIPK1 after residues D324 and D325, respectively, by Caspase-8 separates the RIPK1 kinase domain from the intermediate and death domains. The D325A mutation in mouse RIPK1 leads to embryonic lethality during mouse development^2,3. However, the functional importance of blocking caspase-8-mediated cleavage of RIPK1 on RIPK1 activation in humans is unknown. Here we identify two families with variants in RIPK1 (D324V and D324H) that lead to distinct symptoms of recurrent fevers and lymphadenopathy in an autosomal-dominant manner. Impaired cleavage of RIPK1 D324 variants by Caspase-8 sensitized patients' peripheral blood mononuclear cells to RIPK1 activation, Apoptosis and Necroptosis induced by TNF. The patients showed strong RIPK1-dependent activation of inflammatory signalling pathways and overproduction of inflammatory cytokines and chemokines compared with unaffected controls. Furthermore, we show that expression of the RIPK1 mutants D325V or D325H in mouse embryonic fibroblasts confers not only increased sensitivity to RIPK1 activation-mediated Apoptosis and Necroptosis, but also induction of pro-inflammatory cytokines such as IL-6 and TNF. By contrast, patient-derived fibroblasts showed reduced expression of RIPK1 and downregulated production of Reactive Oxygen Species, resulting in resistance to Necroptosis and Ferroptosis. Together, these data suggest that human non-cleavable RIPK1 variants promote activation of RIPK1, and lead to an autoinflammatory disease characterized by hypersensitivity to Apoptosis and Necroptosis and increased inflammatory response in peripheral blood mononuclear cells, as well as a compensatory mechanism to protect against several pro-death stimuli in fibroblasts.

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