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Hong Dong, Chenxi Liang, Jacob Yount, Shan-Lu Liu, Haitao Wen, O-GlcNAc transferase plays dual antiviral roles by integrating innate immunity and lipid metabolism, The Journal of Immunology, Volume 212, Issue 1_Supplement, May 2024, Page 0176_4285, https://doi.org/10.4049/jimmunol.212.supp.0176.4285
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Abstract
Challenge of host cells with viral pathogens induces robust metabolic reprogramming; however, whether viral component(s) is detected by metabolic enzyme remains completely unknown. Our previous study identified the O-GlcNAc transferase (OGT), an important glucose metabolic enzyme, as a crucial mediator of MAVS-dependent antiviral response. Here, by studying a mouse model with enzyme-inactive OGT, we demonstrate an enzyme-independent function of OGT in limiting influenza A virus (IAV) infection, in addition to its enzyme-dependent effect on MAVS. Biochemical studies reveal a critical antiviral effect of OGT binding with IAV genomic RNA via its N-terminal tetratricopeptide repeats-4 domain. Binding with viral RNA causes a robust translocation of nuclear OGT to cytosolic lipid droplets (LDs) and subsequently antagonizes LD accumulation via destabilizing perilipin 2. This LD-targeting effect of OGT limits IAV replication without altering MAVS signaling. Our findings reveal OGT as a multifaceted metabolic sensor by integrating MAVS-dependent innate immune signaling and lipid metabolism.