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

Abstract

SUMMARY 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 (VSV) 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, OGT-mediated O-GlcNAcylation of the signaling adaptor MAVS on serine 366 (S366) is required for K63-linked ubiquitination of MAVS and subsequent downstream RLR-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 on antiviral innate immunity.

O-GlcNAcylation of SAMHD1 Indicating a Link between Metabolic Reprogramming and Anti-HBV Immunity

“…Because these results demonstrated the importance of protein O-GlcNAcylation in host antiviral innate immunity against HBV, we proposed that an increase in SAMHD1 O-GlcNAcylation by inhibiting OGA activity could be used as a potential antiviral strategy. This is in line with recent results indicating that increased MAVS O-GlcNAcylation is essential to activate host innate immunity against RNA viruses (Li et al , 2018; Song et al , 2019). However, hyper-O-GlcNAcylation has been reported to stabilize several oncogenic factors in several cancers associated with oncogenic virus infection (Makwana et al , 2019).…”

“…Several metabolic pathways, including central carbon metabolism, amino sugar and nucleotide sugar metabolism(Supplementary Fig.1A) were significantly affected. Recent studies have shown that glucose metabolism plays a key role in host antiviral immunity (Li et al , 2018; Song et al , 2019). Hence, we determined the effect of altering glucose metabolism in HepG2-HBV1.3 cells.…”

“…Although we could not exclude the possibility that differences between HBV cell models cause this discrepancy, our results show that increased HBP flux and hyper-O-GlcNAcylation can upregulate host antiviral innate response. Several other studies have reported that HBP and/or protein O-GlcNAcylation promotes host antiviral immunity against RNA viruses, including VSV (Li et al , 2018), influenza virus (Song et al , 2019), and hepatitis C virus (Herzog et al , 2019). Thus, the present study confirms and expands our current understanding of the antiviral activity of HBP and protein O-GlcNAcylation upon DNA virus infection, which is similar to its antiviral activity upon infection by certain RNA viruses.…”

“…O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA) are responsible for the addition and removal of N-acetylglucosamine (GlcNAc) from Ser and Thr residues of target proteins. Several key host proteins involved in immune modulation, including signal transducer and activator of transcription-3 (STAT3), MAVS, and receptor-interacting serine/threonine-protein kinase 3 (RIPK3), are targets for O-GlcNAcylation (Li et al , 2017, 2018, 2019a; Song et al , 2019). However, the mechanism by which HBP-mediated O-GlcNAc modifications enhance antiviral innate immunity remains to be fully understood.…”

LPS induces GFAT2 expression to promote O-GlcNAcylation and attenuate inflammation in macrophages

“…Moreover, whereas several lines of evidence indicate that increased O-GlcNAcylation of signaling proteins in the NFkB pathway potentiates inflammatory processes [26][27][28][29], other studies indicate that increased O-GlcNAcylation may inhibit pro-inflammatory signals [24,30]. More recently, O-GlcNAcylation of the signalling adaptor MAVS in macrophages has been involved in antiviral signalling response [31], whereas increased RIPK3 O-GlcNAcylation was shown to regulate necroptosis signalling upon LPS stimulation [25]. Thus, whereas numerous evidences suggest that modulation of O-GlcNAcylation signalling constitutes an important facet of innate immune response, the mechanisms by which macrophage activation regulates O-GlcNAc, and its consequences on inflammatory processes, remain to be firmly established.…”