OTUD5 promotes innate antiviral and antitumor immunity through deubiquitinating and stabilizing STING

被引：68

作者：

Guo, Yunyun ^{[1
,2
]}

Jiang, Fei ^{[1
,2
]}

Kong, Lingli ^{[1
,2
]}

Wu, Haifeng ^{[1
,2
]}

Zhang, Honghai ^{[1
,2
]}

Chen, Xiaorong ^{[1
,2
]}

Zhao, Jian ^{[1
,2
]}

Cai, Baoshan ^{[1
,2
]}

Li, Yanqi ^{[1
,2
]}

Ma, Chunhong ^{[1
,2
]}

Yi, Fan ^{[3
]}

Zhang, Lei ^{[1
,2
]}

Liu, Bingyu ^{[1
,2
]}

Zheng, Yi ^{[1
,2
]}

Zhang, Lingqiang ^{[4
]}

Gao, Chengjiang ^{[1
,2
]}

机构：

[1] Shandong Univ, Sch Biomed Sci, Key Lab Infect & Immun Shandong Prov, Jinan 250012, Shandong, Peoples R China

[2] Shandong Univ, Sch Biomed Sci, Dept Immunol, Jinan 250012, Shandong, Peoples R China

[3] Shandong Univ, Sch Biomed Sci, Dept Pharmacol, Jinan 250012, Shandong, Peoples R China

[4] Beijing Inst Life, Natl Ctr Prot Sci Beijing, Beijing Proteome Res Ctr, State Key Lab Prote, Beijing 100850, Peoples R China

来源：

CELLULAR & MOLECULAR IMMUNOLOGY | 2021年 / 18卷 / 08期

基金：

中国国家自然科学基金;

关键词：

Antiviral innate immunity; antitumor immunity; STING deubiquitination; OTUD5; CYCLIC GMP-AMP; ACTIVATION; PHOSPHORYLATION; UBIQUITINATION; RECOGNITION; ENZYME; DUBA;

D O I：

10.1038/s41423-020-00531-5

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

Stimulator of interferon genes (STING) is an adaptor protein that is critical for effective innate antiviral and antitumor immunity. The activity of STING is heavily regulated by protein ubiquitination, which is fine-tuned by both E3 ubiquitin ligases and deubiquitinases. Here, we report that the deubiquitinase OTUD5 interacts with STING, cleaves its K48-linked polyubiquitin chains, and promotes its stability. Consistently, knockout of OTUD5 resulted in faster turnover of STING and subsequently impaired type I IFN signaling following cytosolic DNA stimulation. More importantly, Lyz2-CreOtud5(fl/Y)mice and CD11-CreOtud5(fl/Y)mice showed more susceptibility to herpes simplex virus type 1 (HSV-1) infection and faster development of melanomas than their corresponding control littermates, indicating that OTUD5 is indispensable for STING-mediated antiviral and antitumor immunity. Our data suggest that OTUD5 is a novel checkpoint in the cGAS-STING cytosolic DNA sensing pathway.

引用

页码：1945 / 1955

页数：11

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