O-GlcNAc Transferase Links Glucose Metabolism to MAVS-Mediated Antiviral Innate Immunity

• Published in: Cell host & microbe Vol. 24; no. 6; pp. 791 - 803.e6
• Main Authors: Li, Tianliang, Li, Xinghui, Attri, Kuldeep S., Liu, Changhong, Li, Lupeng, Herring, Laura E., Asara, John M., Lei, Yu L., Singh, Pankaj K., Gao, Chengjiang, Wen, Haitao
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 12-12-2018
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Animals; antiviral immunity; Chlorocebus aethiops; Glucose - metabolism; HEK293 Cells; hexosamine biosynthesis pathway (HBP); Hexosamines - metabolism; HT29 Cells; Humans; Immunity, Innate - immunology; MAVS; Mice; Mice, Inbred C57BL; N-Acetylglucosaminyltransferases - genetics; N-Acetylglucosaminyltransferases - metabolism; O-GlcNAc transferase; Rhabdoviridae Infections - immunology; Rhabdoviridae Infections - virology; THP-1 Cells; Vero Cells; Vesicular stomatitis Indiana virus - immunology; MAVS; O-GlcNAc transferase; antiviral immunity; hexosamine biosynthesis pathway (HBP); glucose metabolism
• ISSN: 1931-3128; 1934-6069
• DOI: 10.1016/j.chom.2018.11.001

Increased glucose metabolism in immune cells not only serves as a hallmark feature of acute inflammation but also profoundly affects disease outcome following bacterial infection and tissue damage. However, the role of individual glucose metabolic pathways during viral infection remains largely unknown. Here we demonstrate an essential function of the hexosamine biosynthesis pathway (HBP)-associated O-linked β-N-acetylglucosamine (O-GlcNAc) signaling in promoting antiviral innate immunity. Challenge of macrophages with vesicular stomatitis viruses (VSVs) enhances HBP activity and downstream protein O-GlcNAcylation. Human and murine cells deficient of O-GlcNAc transferase, a key enzyme for protein O-GlcNAcylation, show defective antiviral immune responses upon VSV challenge. Mechanistically, O-GlcNAc transferase-mediated O-GlcNAcylation of the signaling adaptor MAVS on serine 366 is required for K63-linked ubiquitination of MAVS and subsequent downstream retinoic-acid inducible gene-like receptor -antiviral signaling activation. Thus, our study identifies a molecular mechanism by which HBP-mediated O-GlcNAcylation regulates MAVS function and highlights the importance of glucose metabolism in antiviral innate immunity.
[Display omitted]
•Glucose metabolic pathways display enhanced activation upon VSV infection•O-GlcNAc transferase (OGT) enzymatically promotes RLR-mediated antiviral immunity•OGT-mediated O-GlcNAcylation of MAVS on S366 promotes its K63-linked ubiquitination•MAVS K63-linked ubiquitination is critical for its role in RLR-antiviral signaling
Tiangliang et al. demonstrate that enhanced activation of the hexosamine biosynthesis pathway (HBP) occurs upon vesicular stomatitis virus (VSV) infection. HBP activation subsequently promotes RLR-antiviral immunity via O-linked β-N-acetylglucosamine (O-GlcNAc) signaling. Mechanistically, O-GlcNAcylation of the signaling adaptor MAVS on serine 366 is required for its ubiquitination and downstream signaling activation.