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

doi:10.1038/s41586-019-1830-y

GSTDTAP > 地球科学

DOI	10.1038/s41586-019-1830-y
	A dominant autoinflammatory disease caused by non-cleavable variants of RIPK1
	Tao, Panfeng 1; Sun, Jinqiao 2; Wu, Zheming 3; Wang, Shihao 1; Wang, Jun 1; Li, Wanjin 4; Pan, Heling 3; Bai, Renkui 5; Zhang, Jiahui 1; Wang, Ying 2; Lee, Pui Y.6; Ying, Wenjing 2; Zhou, Qinhua 2; Hou, Jia 2; Wang, Wenjie 2; Sun, Bijun 2; Yang, Mi 2; Liu, Danru 2; Fang, Ran 1; Han, Huan 1; Yang, Zhaohui 1; Huang, Xin 3; Li, Haibo 7; Deuitch, Natalie 8; Zhang, Yuan 9; Dissanayake, Dilan 10,11; Haude, Katrina 5; McWalter, Kirsty 5; Roadhouse, Chelsea 12; MacKenzie, Jennifer J.12,13; Laxer, Ronald M.10,11,14; Aksentijevich, Ivona 15; Yu, Xiaomin 1; Wang, Xiaochuan 2; Yuan, Junying 4; Zhou, Qing 1,16
	2020-05-01
发表期刊	NATURE
ISSN	0028-0836
EISSN	1476-4687
出版年	2020
卷号	577 期号:7788 页码:109-+
文章类型	Article
语种	英语
国家	Peoples R China; USA; Canada
英文关键词	Activation of RIPK1 controls TNF-mediated apoptosis, necroptosis and inflammatory pathways(1). 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 autosomaldominant 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.
领域	地球科学 ; 气候变化 ; 资源环境
收录类别	SCI-E
WOS记录号	WOS:000505617400035
WOS关键词	CELL-DEATH ; MUTATIONS ; NECROPTOSIS ; KINASE ; METABOLISM ; ACTIVATION
WOS类目	Multidisciplinary Sciences
WOS研究方向	Science & Technology - Other Topics
引用统计
文献类型	期刊论文
条目标识符	http://119.78.100.173/C666/handle/2XK7JSWQ/281070
专题	地球科学资源环境科学气候变化
作者单位	1.Zhejiang Univ, Inst Life Sci, MOE Key Lab Biosyst Homeostasis & Protect, Hangzhou, Peoples R China; 2.Fudan Univ, Childrens Hosp, Dept Clin Immunol, Shanghai, Peoples R China; 3.Chinese Acad Sci, Shanghai Inst Organ Chem, Interdisciplinary Res Ctr Biol & Chem, Shanghai, Peoples R China; 4.Harvard Med Sch, Dept Cell Biol, Boston, MA 02115 USA; 5.GeneDx, Gaithersburg, MD USA; 6.Boston Childrens Hosp, Div Immunol, Boston, MA USA; 7.Ningbo Women & Childrens Hosp, Ningbo, Zhejiang, Peoples R China; 8.Stanford Univ, Dept Human Genet, Sch Med, Stanford, CA 94305 USA; 9.NIAID, Lab Allerg Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA; 10.Hosp Sick Children, Dept Paediat, Div Rheumatol, Toronto, ON, Canada; 11.Univ Toronto, Toronto, ON, Canada; 12.McMaster Childrens Hosp, Dept Pediat, Hamilton, ON, Canada; 13.McMaster Univ, Hamilton, ON, Canada; 14.Hosp Sick Children, Dept Med, Div Rheumatol, Toronto, ON, Canada; 15.NHGRI, Inflammatory Dis Sect, NIH, Bethesda, MD 20892 USA; 16.Zhejiang Univ, Womens Hosp, Sch Med, Hangzhou, Peoples R China
推荐引用方式 GB/T 7714	Tao, Panfeng,Sun, Jinqiao,Wu, Zheming,et al. A dominant autoinflammatory disease caused by non-cleavable variants of RIPK1[J]. NATURE,2020,577(7788):109-+.
APA	Tao, Panfeng.,Sun, Jinqiao.,Wu, Zheming.,Wang, Shihao.,Wang, Jun.,...&Zhou, Qing.(2020).A dominant autoinflammatory disease caused by non-cleavable variants of RIPK1.NATURE,577(7788),109-+.
MLA	Tao, Panfeng,et al."A dominant autoinflammatory disease caused by non-cleavable variants of RIPK1".NATURE 577.7788(2020):109-+.