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

Panfeng Tao, Jinqiao Sun, Zheming Wu, Shihao Wang, Jun Wang, Wanjin Li, Heling Pan, Renkui Bai, Jiahui Zhang, Ying Wang, Pui Y. Lee, Wenjing Ying, Qinhua Zhou, Jia Hou, Wenjie Wang, Bijun Sun, Mi Yang, Danru Liu, Ran Fang, Huan Han, Zhaohui Yang, Xin Huang, Haibo Li, Natalie Deuitch, Yuan Zhang, Dilan Dissanayake, Katrina Haude, Kirsty McWalter, Chelsea Roadhouse, Jennifer J. MacKenzie, Ronald M. Laxer, Ivona Aksentijevich, Xiaomin Yu (), Xiaochuan Wang (), Junying Yuan () and Qing Zhou ()
Additional contact information
Panfeng Tao: Zhejiang University
Jinqiao Sun: Children’s Hospital of Fudan University
Zheming Wu: Chinese Academy of Sciences
Shihao Wang: Zhejiang University
Jun Wang: Zhejiang University
Wanjin Li: Harvard Medical School
Heling Pan: Chinese Academy of Sciences
Renkui Bai: GeneDx
Jiahui Zhang: Zhejiang University
Ying Wang: Children’s Hospital of Fudan University
Pui Y. Lee: Boston Children’s Hospital
Wenjing Ying: Children’s Hospital of Fudan University
Qinhua Zhou: Children’s Hospital of Fudan University
Jia Hou: Children’s Hospital of Fudan University
Wenjie Wang: Children’s Hospital of Fudan University
Bijun Sun: Children’s Hospital of Fudan University
Mi Yang: Children’s Hospital of Fudan University
Danru Liu: Children’s Hospital of Fudan University
Ran Fang: Zhejiang University
Huan Han: Zhejiang University
Zhaohui Yang: Zhejiang University
Xin Huang: Chinese Academy of Sciences
Haibo Li: Ningbo Women and Children’s Hospital
Natalie Deuitch: Stanford University School of Medicine
Yuan Zhang: National Institutes of Health
Dilan Dissanayake: The Hospital for Sick Children and the University of Toronto
Katrina Haude: GeneDx
Kirsty McWalter: GeneDx
Chelsea Roadhouse: McMaster Children’s Hospital
Jennifer J. MacKenzie: McMaster Children’s Hospital
Ronald M. Laxer: The Hospital for Sick Children and the University of Toronto
Ivona Aksentijevich: National Institutes of Health
Xiaomin Yu: Zhejiang University
Xiaochuan Wang: Children’s Hospital of Fudan University
Junying Yuan: Harvard Medical School
Qing Zhou: Zhejiang University

Nature, 2020, vol. 577, issue 7788, 109-114

Abstract: 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 development2,3. 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.

Date: 2020
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DOI: 10.1038/s41586-019-1830-y

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