The ubiquitin E3 ligase TRIM10 promotes STING aggregation and activation in the Golgi apparatus.
The ubiquitin E3 ligase TRIM10 promotes STING aggregation and activation in the Golgi apparatus.
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DOI：
10.1016/j.celrep.2023.112306
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发表时间：
2023-03
期刊：
影响因子：
8.8
通讯作者：
Lingli Kong;Chao Sui;Tian Chen;Lei Zhang;Wei Zhao;Y. Zheng;Bingyu Liu;Xiaochen Cheng;Chengjiang Gao
中科院分区：
文献类型：
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作者：
Lingli Kong;Chao Sui;Tian Chen;Lei Zhang;Wei Zhao;Y. Zheng;Bingyu Liu;Xiaochen Cheng;Chengjiang Gao
STING 是一种调节先天免疫的内质网驻留蛋白。与环鸟苷单磷酸-AMP (cGAMP) 结合后，STING 从内质网 (ER) 易位至高尔基体，刺激 TBK1 和 IRF3 激活，导致 I 型干扰素的表达。然而，有关 STING 激活的确切机制在很大程度上仍然是个谜。在这里，我们将三联基序 10 (TRIM10) 确定为 STING 信号传导的正调节因子。 TRIM10 缺陷型巨噬细胞在双链 DNA (dsDNA) 或 cGAMP 刺激下表现出 I 型干扰素产生减少，并且对单纯疱疹病毒 1 (HSV-1) 感染的抵抗力降低。此外，TRIM10 缺陷的小鼠更容易受到 HSV-1 感染，并表现出更快的黑色素瘤生长。从机制上讲，TRIM10 与 STING 结合，并在 K289 和 K370 处催化 STING 的 K27 和 K29 连接的多泛素化，从而促进 STING 从 ER 运输到高尔基体、形成 STING 聚集体以及将 TBK1 招募到 STING，最终增强 STING 依赖性 I 型干扰素反应。我们的研究将 TRIM10 定义为 cGAS-STING 介导的抗病毒和抗肿瘤免疫的关键激活剂。
STING is an endoplasmic reticulum-resident protein regulating innate immunity. After binding with cyclic guanosine monophosphate-AMP (cGAMP), STING translocates from the endoplasmic reticulum (ER) to the Golgi apparatus to stimulate TBK1 and IRF3 activation, leading to expression of type I interferon. However, the exact mechanism concerning STING activation remains largely enigmatic. Here, we identify tripartite motif 10 (TRIM10) as a positive regulator of STING signaling. TRIM10-deficient macrophages exhibit reduced type I interferon production upon double-stranded DNA (dsDNA) or cGAMP stimulation and decreased resistance to herpes simplex virus 1 (HSV-1) infection. Additionally, TRIM10-deficient mice are more susceptible to HSV-1 infection and exhibit faster melanoma growth. Mechanistically, TRIM10 associates with STING and catalyzes K27- and K29-linked polyubiquitination of STING at K289 and K370, which promotes STING trafficking from the ER to the Golgi apparatus, formation of STING aggregates, and recruitment of TBK1 to STING, ultimately enhancing the STING-dependent type I interferon response. Our study defines TRIM10 as a critical activator in cGAS-STING-mediated antiviral and antitumor immunity.