Autophagy and interferon (IFN)-mediated innate immunity are critical antiviral defence mechanisms, and recent evidence indicated that tripartite motif (TRIM) proteins are important regulators of both processes. Although the role of TRIM proteins in modulating antiviral cytokine responses has been well established, much less is known about their involvement in autophagy in response to different viral pathogens. Through a targeted RNAi screen examining the relevance of selected TRIM proteins in autophagy induced by herpes simplex virus 1 (HSV-1), encephalomyocarditis virus (EMCV) and influenza A virus (IAV), we identified several TRIM proteins that regulate autophagy in a virus-species-specific manner, as well as a few TRIM proteins that were essential for autophagy triggered by all three viruses and rapamycin, among them TRIM23. TRIM23 was critical for autophagy-mediated restriction of multiple viruses, and this activity was dependent on both its RING E3 ligase and ADP-ribosylation factor (ARF) GTPase activity. Mechanistic studies revealed that unconventional K27-linked auto-ubiquitination of the ARF domain is essential for the GTP hydrolysis activity of TRIM23 and activation of TANK-binding kinase 1 (TBK1) by facilitating its dimerization and ability to phosphorylate the selective autophagy receptor p62. Our work identifies the TRIM23-TBK1-p62 axis as a key component of selective autophagy and further reveals a role for K27-linked ubiquitination in GTPase-dependent TBK1 activation.

中文翻译：

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TRIM23 通过激活 TBK1 介导病毒诱导的自噬。


自噬和干扰素 (IFN) 介导的先天免疫是重要的抗病毒防御机制，最近的证据表明三联基序 (TRIM) 蛋白是这两个过程的重要调节因子。尽管 TRIM 蛋白在调节抗病毒细胞因子反应中的作用已得到充分证实，但人们对它们在响应不同病毒病原体的自噬中的参与知之甚少。通过靶向 RNAi 筛选检查选定的 TRIM 蛋白在单纯疱疹病毒 1 (HSV-1)、脑心肌炎病毒 (EMCV) 和甲型流感病毒 (IAV) 诱导的自噬中的相关性，我们鉴定了几种调节病毒自噬的 TRIM 蛋白-物种特异性方式，以及一些对所有三种病毒和雷帕霉素触发的自噬至关重要的 TRIM 蛋白，其中包括 TRIM23。 TRIM23 对于自噬介导的多种病毒限制至关重要，这种活性依赖于其 RING E3 连接酶和 ADP 核糖基化因子 (ARF) GTP 酶活性。机制研究表明，非常规的 K27 连接的 ARF 结构域的自动泛素化对于 TRIM23 的 GTP 水解活性和通过促进其二聚化和磷酸化选择性自噬受体 p62 的能力来激活 TANK 结合激酶 1 (TBK1) 至关重要。我们的工作将 TRIM23-TBK1-p62 轴确定为选择性自噬的关键组成部分，并进一步揭示了 K27 连接的泛素化在 GTPase 依赖性 TBK1 激活中的作用。