O -GlcNAc transferase promotes influenza A virus-induced cytokine storm by targeting interferon regulatory factor-5

• Published in: Science advances Vol. 6; no. 16; p. eaaz7086
• Main Authors: Wang, Qiming, Fang, Peining, He, Rui, Li, Mengqi, Yu, Haisheng, Zhou, Li, Yi, Yu, Wang, Fubing, Rong, Yuan, Zhang, Yi, Chen, Aidong, Peng, Nanfang, Lin, Yong, Lu, Mengji, Zhu, Ying, Peng, Guoping, Rao, Liqun, Liu, Shi
• Format: Journal Article
• Language: English
• Published: United States American Association for the Advancement of Science 01.04.2020
• Subjects: Cytokine Release Syndrome; Cytokines; Hexosamines; Humans; Influenza A virus; Interferon Regulatory Factors; N-Acetylglucosaminyltransferases; SciAdv r-articles; Signal Transduction; Virology
• ISSN: 2375-2548; 2375-2548
• DOI: 10.1126/sciadv.aaz7086

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.