<i>O</i> -GlcNAc transferase promotes influenza A virus–induced cytokine storm by targeting interferon regulatory factor–5

Abstract

In this study, we demonstrated an essential function of the hexosamine biosynthesis pathway (HBP)-associated <i>O</i>-linked β-<i>N</i>-acetylglucosamine (<i>O</i>-GlcNAc) signaling in influenza A virus (IAV)-induced cytokine storm. <i>O</i>-GlcNAc transferase (OGT), a key enzyme for protein <i>O</i>-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 <i>O</i>-GlcNAcylation of IRF5 on serine-430. <i>O</i>-GlcNAcylation of IRF5 is required for K63-linked ubiquitination of IRF5 and subsequent cytokine production. Analysis of clinical samples revealed that IRF5 is <i>O</i>-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 <i>O</i>-GlcNAcylation regulates IRF5 function during IAV infection, highlighting the importance of glucose metabolism in IAV-induced cytokine storm.