GlcNAc 转移酶通过靶向干扰素调节因子 5 促进甲型流感病毒诱导的细胞因子风暴。
-GlcNAc transferase promotes influenza A virus-induced cytokine storm by targeting interferon regulatory factor-5.
机构信息
College of Bioscience and Biotechnology, Human Agricultural University, Changsha 410128, Human Province, China.
State Key Laboratory of Virology, Modern Virology Research Center, College of Life sciences, Wuhan University, Wuhan 430072, China.
出版信息
Sci Adv. 2020 Apr 15;6(16):eaaz7086. doi: 10.1126/sciadv.aaz7086. eCollection 2020 Apr.
In this study, we demonstrated an essential function of the hexosamine biosynthesis pathway (HBP)-associated -linked β--acetylglucosamine (-GlcNAc) signaling in influenza A virus (IAV)-induced cytokine storm. -GlcNAc transferase (OGT), a key enzyme for protein -GlcNAcylation, mediated IAV-induced cytokine production. Upon investigating the mechanisms driving this event, we determined that IAV induced OGT to bind to interferon regulatory factor-5 (IRF5), leading to -GlcNAcylation of IRF5 on serine-430. -GlcNAcylation of IRF5 is required for K63-linked ubiquitination of IRF5 and subsequent cytokine production. Analysis of clinical samples revealed that IRF5 is -GlcNAcylated, and higher levels of proinflammatory cytokines correlated with higher levels of blood glucose in IAV-infected patients. We identified a molecular mechanism by which HBP-mediated -GlcNAcylation regulates IRF5 function during IAV infection, highlighting the importance of glucose metabolism in IAV-induced cytokine storm.
在这项研究中，我们证明了己糖胺生物合成途径（HBP）相关的β-连接 N-乙酰氨基葡萄糖（-GlcNAc）信号在甲型流感病毒（IAV）诱导的细胞因子风暴中的重要作用。-GlcNAc 转移酶（OGT）是蛋白质-O-GlcNAcylation 的关键酶，介导 IAV 诱导的细胞因子产生。在研究驱动这一事件的机制时，我们确定 IAV 诱导 OGT 与干扰素调节因子 5（IRF5）结合，导致 IRF5 丝氨酸 430 上的-O-GlcNAcylation。IRF5 的-O-GlcNAcylation 是 K63 连接的泛素化 IRF5 和随后的细胞因子产生所必需的。对临床样本的分析表明，IRF5 被-O-GlcNAcylation，IAV 感染患者血液中更高水平的促炎细胞因子与更高水平的血糖相关。我们确定了 HBP 介导的-O-GlcNAcylation 在 IAV 感染期间调节 IRF5 功能的分子机制，强调了葡萄糖代谢在 IAV 诱导的细胞因子风暴中的重要性。
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