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

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

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 de...

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Bibliographic Details
Published in:Cellular & molecular immunology 2021-08, Vol.18 (8), p.1945-1955
Main Authors: Guo, Yunyun, Jiang, Fei, Kong, Lingli, Wu, Haifeng, Zhang, Honghai, Chen, Xiaorong, Zhao, Jian, Cai, Baoshan, Li, Yanqi, Ma, Chunhong, Yi, Fan, Zhang, Lei, Liu, Bingyu, Zheng, Yi, Zhang, Lingqiang, Gao, Chengjiang
Format: Article
Language:eng
Subjects:
Animals
Dendritic cells
Deoxyribonucleic acid
DNA
Herpes Simplex
Herpes viruses
Herpesvirus 1, Human
Immunity, Innate
Immunology
Infections
Interferon
Kinases
Laboratories
Membrane Proteins - metabolism
Mice
Ovaries
Pathogens
Proteins
Signal transduction
Ubiquitin
Ubiquitin-Specific Proteases - metabolism
Ubiquitination
Viral infections
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Summary: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-Cre Otud5 mice and CD11-Cre Otud5 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.
ISSN:1672-7681
2042-0226