自噬
细胞生物学
坦克结合激酶1
生物
袋3
GTP酶
干扰素
泛素连接酶
泛素
先天免疫系统
病毒
化学
病毒学
磷酸化
生物化学
蛋白激酶A
受体
基因
细胞凋亡
丝裂原活化蛋白激酶激酶
作者
Konstantin M. J. Sparrer,Sebastian Gableske,Matthew A. Zurenski,Zachary M. Parker,Florian Full,Gavin J. Baumgart,Jirō Katō,Gustavo Pacheco‐Rodriguez,Chengyu Liang,Owen Pornillos,Joel Moss,Martha Vaughan,Michaela U. Gack
出处
期刊:Nature microbiology
日期:2017-09-04
卷期号:2 (11): 1543-1557
被引量:149
标识
DOI:10.1038/s41564-017-0017-2
摘要
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.
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