O-GlcNAc transferase plays dual antiviral roles by integrating innate immunity and lipid metabolism

作者：Hong Dong, Chenxi Liang, Junjie Zhang, Weidong Wu, Nitesh Kumar, Zihao Liu, Yajun Sun, Zhiwei Liao, Xiaolin Cheng, Yanbao Yu, Yong Zhang, Michael J. Holtzman, Jiànróng Lǐ, Kymberly M. Gowdy, Paul G. Thomas, Jovica D. Badjić, Anjun Ma, Qin Ma, Jacob S. Yount, Shan‐Lu Liu, Haitao Wen · 发表于：Nature Communications · 年份：2025 · DOI：10.1038/s41467-025-63085-y · 被引用次数：8 · 研究领域：Glycosylation and Glycoproteins Research、Galectins and Cancer Biology、interferon and immune responses

Viral infection induces robust reprogramming of metabolic pathways in host cells. However, whether host metabolic enzymes detect viral components remains unknown. Our group and others previously identified O-GlcNAc transferase (OGT), an important glucose metabolic enzyme, as a crucial mediator of the antiviral immune responses. Here, by studying a mouse model with a catalytically impaired OGT, we discover a catalytic activity-independent function of OGT in restraining influenza A virus (IAV) infection in addition to its catalytic activity-dependent effect on MAVS-mediated antiviral immunity. Biochemical studies reveal a critical antiviral effect based on OGT interacting with IAV genomic RNA that requires its N-terminal tetracopeptide repeat-4 motif. This interaction causes the translocation of nuclear OGT to cytosolic lipid droplets (LDs) to destabilize LDs-coating perilipin 2, thereby limiting LDs accumulation and in turn virus replication. In sum, our findings reveal OGT as a multifaceted metabolic sensor that integrates MAVS signaling and lipid metabolism to combat viral infection. O-GlcNAc transferase (OGT) mediates antiviral host immune response. Here, the authors identify a catalytic activity-independent function of OGT in restraining influenza A virus replication by translocating to lipid droplets and limiting their accumulation following interaction with viral RNA.