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Summary: It is known that lethal viruses profoundly manipulate host metabolism, but how the metabolism alternation affects the immediate host antiviral immunity remains elusive. Here, we report that the O-GlcNAcylation of mitochondrial antiviral-signaling protein (MAVS), a key mediator of interferon signaling, is a critical regulation to activate the host innate immunity against RNA viruses. We show that O-GlcNAcylation depletion in myeloid cells renders the host more susceptible to virus infection both in vitro and in vivo. Mechanistically, we demonstrate that MAVS O-GlcNAcylation is required for virus-induced MAVS K63-linked ubiquitination, thereby facilitating IRF3 activation and IFNβ production. We further demonstrate that D-glucosamine, a commonly used dietary supplement, effectively protects mice against a range of lethal RNA viruses, including human influenza virus. Our study highlights a critical role of O-GlcNAcylation in regulating host antiviral immunity and validates D-glucosamine as a potential therapeutic for virus infections. : Mitochondrial antiviral-signaling protein (MAVS) plays a key role in host antiviral innate immunity. Song et al. demonstrate that O-GlcNAcylation of MAVS is critical in RNA virus-induced innate immune response and validate D-glucosamine as a potential broad-spectrum antiviral therapeutic. Keywords: MAVS, O-GlcNAcylation, glucosamine, RNA virus, influenza, interferon, antiviral immunity