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OTUD5 promotes innate antiviral and antitumor immunity through deubiquitinating and stabilizing STING.
Cellular & Molecular Immunology ( IF 24.1 ) Pub Date : 2020-09-02 , DOI: 10.1038/s41423-020-00531-5
Yunyun Guo 1 , Fei Jiang 1 , Lingli Kong 1 , Haifeng Wu 1 , Honghai Zhang 1 , Xiaorong Chen 1 , Jian Zhao 1 , Baoshan Cai 1 , Yanqi Li 1 , Chunhong Ma 1 , Fan Yi 2 , Lei Zhang 1 , Bingyu Liu 1 , Yi Zheng 1 , Lingqiang Zhang 3 , Chengjiang Gao 1
Affiliation  

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 Otud5fl/Y mice and CD11-Cre Otud5fl/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.



中文翻译:

OTUD5 通过去泛素化和稳定 STING 来促进先天性抗病毒和抗肿瘤免疫。

干扰素基因刺激物 (STING) 是一种衔接蛋白,对有效的先天抗病毒和抗肿瘤免疫至关重要。STING 的活性受到蛋白质泛素化的严格调节,蛋白质泛素化由 E3 泛素连接酶和去泛素酶进行微调。在这里,我们报告去泛素酶 OTUD5 与 STING 相互作用,切割其 K48 连接的多泛素链,并促进其稳定性。一致地,敲除 OTUD5 导致 STING 的更快更新,并随后在细胞溶质 DNA 刺激后损害 I 型 IFN 信号传导。更重要的是,Lyz2-Cre Otud5 fl/Y小鼠和 CD11-Cre Otud5 fl/Y与相应的对照同窝小鼠相比,小鼠对单纯疱疹病毒 1 型 (HSV-1) 感染的敏感性更高,黑色素瘤的发展速度更快,这表明 OTUD5 对于 STING 介导的抗病毒和抗肿瘤免疫是必不可少的。我们的数据表明,OTUD5 是 cGAS-STING 胞质 DNA 传感通路中的一个新检查点。

更新日期:2020-09-02
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