OTUD5 promotes innate antiviral and antitumor immunity through deubiquitinating and stabilizing STING
OTUD5 promotes innate antiviral and antitumor immunity through deubiquitinating and stabilizing STING
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OTUD5 通过去泛素化和稳定 STING 来促进先天抗病毒和抗肿瘤免疫
DOI：
10.1038/s41423-020-00531-5
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发表时间：
2020-09-02
影响因子：
24.1
通讯作者：
Gao, Chengjiang
中科院分区：
文献类型：
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作者：
Guo, Yunyun;Jiang, Fei;Gao, Chengjiang
干扰素基因刺激物(STING)是一种适配蛋白，对有效的天然抗病毒和抗肿瘤免疫至关重要。蛋白泛素化在很大程度上调节了STING的活性，E3泛素连接酶和去泛素酶都对其进行了微调。在这里，我们报道了脱泛素酶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更快的周转，随后在胞浆DNA刺激后I型干扰素信号受损。更重要的是，Lyz2-CreOtud5fl/Y小鼠和CD11-CreOtud5fl/Y小鼠对单纯疱疹病毒1型(HSV-1)感染的易感性和黑色素瘤的发生较快，表明OTUD5在刺痛介导的抗病毒和抗肿瘤免疫中是不可或缺的。我们的数据表明，OTUD5是cGAS刺激性胞浆DNA传感途径中的一个新的检查点。
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-CreOtud5fl/Ymice and CD11-CreOtud5fl/Ymice 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.