气候变化领域集成服务门户(CCPortal): Immune dysregulation in SHARPIN-deficient mice is dependent on CYLD-mediated cell death

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DOI	10.1073/pnas.2001602118
	Immune dysregulation in SHARPIN-deficient mice is dependent on CYLD-mediated cell death
	Ang R.L.; Chan M.; Legarda D.; Sundberg J.P.; Sun S.-C.; Gillespie V.L.; Chun N.; Heeger P.S.; Xiong H.; Lira S.A.; Ting A.T.
发表日期	2021
ISSN	1091-6490
卷号	118 期号:50
英文摘要	SHARPIN, together with RNF31/HOIP and RBCK1/HOIL1, form the linear ubiquitin chain assembly complex (LUBAC) E3 ligase that catalyzes M1-linked polyubiquitination. Mutations in RNF31/HOIP and RBCK/HOIL1 in humans and Sharpin in mice lead to autoinflammation and immunodeficiency, but the mechanism underlying the immune dysregulation remains unclear. We now show that the phenotype of the Sharpincpdm/cpdm mice is dependent on CYLD, a deubiquitinase previously shown to mediate removal of K63-linked polyubiquitin chains. Dermatitis, disrupted splenic architecture, and loss of Peyer's patches in the Sharpincpdm/cpdm mice were fully reversed in Sharpincpdm/cpdm Cyld-/- mice. We observed enhanced association of RIPK1 with the death-signaling Complex II following TNF stimulation in Sharpincpdm/cpdm cells, a finding dependent on CYLD since we observed reversal in Sharpincpdm/cpdm Cyld-/- cells. Enhanced RIPK1 recruitment to Complex II in Sharpincpdm/cpdm cells correlated with impaired phosphorylation of CYLD at serine 418, a modification reported to inhibit its enzymatic activity. The dermatitis in the Sharpincpdm/cpdm mice was also ameliorated by the conditional deletion of Cyld using LysM-cre or Cx3cr1-cre indicating that CYLD-dependent death of myeloid cells is inflammatory. Our studies reveal that under physiological conditions, TNF- and RIPK1-dependent cell death is suppressed by the linear ubiquitin-dependent inhibition of CYLD. The Sharpincpdm/cpdm phenotype illustrates the pathological consequences when CYLD inhibition fails.
英文关键词	apoptosis; inflammation; ripoptocide; TNF; ubiquitin
语种	英语
scopus关键词	CYLD protein, mouse; signal peptide; Sipl1 protein, mouse; ubiquitin carboxyl terminal hydrolase CYLD; animal; bone marrow cell; cell death; cytology; female; fibroblast; gene expression regulation; genetics; immunology; inflammation; knockout mouse; male; mammalian embryo; metabolism; mouse; phosphorylation; physiology; skin disease; ubiquitination; Animals; Cell Death; Deubiquitinating Enzyme CYLD; Embryo, Mammalian; Female; Fibroblasts; Gene Expression Regulation; Inflammation; Intracellular Signaling Peptides and Proteins; Male; Mice; Mice, Knockout; Myeloid Cells; Phosphorylation; Skin Diseases; Ubiquitination
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/250928
作者单位	Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029; ting.adrian@mayo.edu; Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, NY, NY 10029; Department of Immunology, Mayo Clinic, Rochester; Jackson Laboratory; Department of Immunology, MD Anderson Cancer Center, University of Texas, Houston, TX 77030; Center for Comparative Medicine and Surgery, Icahn School of Medicine at Mount Sinai, NY, NY 10029; Department of Medicine, Translational Transplant Research Center, Recanati Miller Transplant Institute, Icahn School of Medicine at Mount Sinai, NY, NY 10029; Tisch Cancer Institute, Department of Medicine, Icahn School of Medicine at Mount Sinai, NY, NY 10029; Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029; rang.phd776@gmail.com ting.adrian@mayo.edu
推荐引用方式 GB/T 7714	Ang R.L.,Chan M.,Legarda D.,et al. Immune dysregulation in SHARPIN-deficient mice is dependent on CYLD-mediated cell death[J],2021,118(50).
APA	Ang R.L..,Chan M..,Legarda D..,Sundberg J.P..,Sun S.-C..,...&Ting A.T..(2021).Immune dysregulation in SHARPIN-deficient mice is dependent on CYLD-mediated cell death.Proceedings of the National Academy of Sciences of the United States of America,118(50).
MLA	Ang R.L.,et al."Immune dysregulation in SHARPIN-deficient mice is dependent on CYLD-mediated cell death".Proceedings of the National Academy of Sciences of the United States of America 118.50(2021).