O-GlcNAc transferase promotes influenza A virus-induced cytokine storm by targeting interferon regulatory factor-5
O-GlcNAc transferase promotes influenza A virus-induced cytokine storm by targeting interferon regulatory factor-5
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O-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
DOI：
10.1126/sciadv.aaz7086
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发表时间：
2020-04-01
期刊：
影响因子：
13.6
通讯作者：
Liu, Shi
中科院分区：
文献类型：
--
作者：
Wang, Qiming;Fang, Peining;Liu, Shi
在这项研究中，我们证明了己糖胺生物合成途径（HBP）相关的O-连接的β-N-乙酰葡萄糖胺（O-GlcNAc）信号在甲型流感病毒（IAV）诱导的细胞因子风暴的基本功能。O-GlcNAc转移酶（OGT）是蛋白质O-GlcNAc酰化的关键酶，介导IAV诱导的细胞因子产生。在研究驱动该事件的机制后，我们确定IAV诱导OGT与干扰素调节因子-5（IRF 5）结合，导致IRF 5在丝氨酸-430上的O-GlcNAc酰化。IRF 5的O-GlcNAc酰化是IRF 5的K63连接的泛素化和随后的细胞因子产生所必需的。临床样本的分析显示IRF 5是O-GlcNAc酰化的，并且在IAV感染的患者中较高水平的促炎细胞因子与较高水平的血糖相关。我们确定了一种分子机制，通过这种机制，HBP介导的O-GlcNAc酰化在IAV感染期间调节IRF 5功能，突出了葡萄糖代谢在IAV诱导的细胞因子风暴中的重要性。
In this study, we demonstrated an essential function of the hexosamine biosynthesis pathway (HBP)-associated O-linked beta-N-acetylglucosamine (O-GlcNAc) signaling in influenza A virus (IAV)-induced cytokine storm. O-GlcNAc transferase (OGT), a key enzyme for protein O-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 O-GlcNAcylation of IRF5 on serine-430.O-GlcNAcylation of IRF5 is required for K63-linked ubiquitination of IRF5 and subsequent cytokine production. Analysis of clinical samples revealed that IRF5 is O-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 O-GlcNAcylation regulates IRF5 function during IAV infection, highlighting the importance of glucose metabolism in IAV-induced cytokine storm.