MAVS O-GlcNAcylation Is Essential for Host Antiviral Immunity against Lethal RNA Viruses

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. [Display omitted] •O-GlcNAc transferase (OGT) deficiency impairs host defense against RNA virus•Mitochondrial antiviral-signaling protein (MAVS) is O-GlcNAcylated at multiple sites•O-GlcNAcylation of MAVS is critical for the activation of interferon signaling•D-glucosamine protects mice against lethal RNA viruses 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.