O-GlcNAcylation: A Nutrient-Sensitive Metabolic Rheostat in Antiviral Immunity and Viral Pathogenesis

Abstract

Viruses account for the most abundant biological entities in the biosphere and can be either symbiotic or pathogenic. While pathogenic viruses have developed strategies to evade immunity, the host immune system has evolved overlapping and redundant defenses to sense and fight viral infections. Nutrition and metabolic needs sculpt viral-host interactions and determine the course and outcomes of the infection. In this review, we focus on the hexosamine biosynthesis pathway (HBP), a nutrient-sensing pathway that controls immune responses and host-viral interactions. The HBP converges on O-GlcNAcylation, a dynamic post-translational modification of cellular proteins, that emerged as a critical effector of immune cell development, differentiation, and effector functions. We present a broad overview of uncovered O-GlcNAc substrates identified in the context of viral infections and with a functional impact on antiviral immunity and viral restriction, or conversely on exacerbating viral-induced pathologic inflammation or viral oncogenesis. We discuss the clinical implications of these findings, current limitations, and future perspectives to harness this pathway for therapeutic purposes.

Keywords: glycosylation; host–pathogen interaction; immunometabolism; infection; inflammation; innate immunity; nutrient sensing; pattern-recognition receptors; post-translational modification; virus.

Figure 1

The hexosamine biosynthesis pathway (HBP) links nutrient availability to dynamic protein O-GlcNAcylation. The HBP integrates inputs from multiple nutrient and metabolic sources to generate UDP-GlcNAc, the donor substrate for protein O-GlcNAcylation. A fraction of glucose entering glycolysis is diverted at fructose-6-phosphate (F6P), which, together with glutamine, fuels GFAT/GFPT, the rate-limiting step of the pathway. Additional inputs are provided by acetyl-CoA from the tricarboxylic acid (TCA) cycle, uridine triphosphate (UTP) from pyrimidine biosynthesis, and nutrient-sensitive regulators (AMPK, mTOR, AKT, HIF1, MYC). The resulting UDP-GlcNAc is utilized by O-GlcNAc transferase (OGT) to modify serine/threonine residues on nuclear, cytoplasmic, and mitochondrial proteins, while O-GlcNAcase (OGA) removes the modification.

Figure 2

O-GlcNAcylation in innate antiviral signaling. Pattern recognition receptors (PRRs) such as cGAS, RIG-I, MDA5, and TLRs detect viral nucleic acids and trigger downstream signaling through STING, MAVS, and adaptor complexes that converge on IRF3/5/7 and NF-κB to drive type I interferon and pro-inflammatory cytokine production. O-GlcNAc transferase (OGT) and the hexosamine biosynthesis pathway (HBP) integrate nutrient availability with these antiviral pathways by directly modifying central effectors. MAVS O-GlcNAcylation promotes K63-linked ubiquitination and antiviral signaling, while UBXN1 O-GlcNAcylation relieves its inhibitory effect on MAVS. STING requires O-GlcNAcylation for activation and IFN induction. IRF5 O-GlcNAcylation drives TRAF6-mediated ubiquitination and cytokine storm responses in severe influenza, whereas NF-κB and TAB1 O-GlcNAcylation promote inflammatory gene expression. STAT1 O-GlcNAcylation, which counteracts β-hydroxybutyrylation, is required for efficient IFNAR signaling. CUL5-mediated K48-linked ubiquitination mediates OGT degradation.

Figure 3

O-GlcNAcylation modulates multiple steps of the viral life cycle and viral oncogenesis. O-GlcNAcylation stabilizes the antiviral factor SAMHD1, thereby enhancing restriction of HIV-1 and HBV. In HBV infection, O-GlcNAcylation of the m⁶A reader YTHDF2 promotes stabilization and binding to MCM2/5 transcripts, supporting viral oncogenesis. In influenza A virus (IAV), OGT restricts replication by targeting lipid droplet metabolism via PLIN2 degradation, while in SARS-CoV-2, O-GlcNAcylation of the spike protein enhances stability and particle packaging. In HTLV-1, the viral oncoprotein Tax inhibits OGA, elevating CREB O-GlcNAcylation and driving proviral transcription. HPV E6/E7 stimulates OGT expression, leading to c-MYC O-GlcNAcylation and stabilization, which sustains cellular transformation. In KSHV, O-GlcNAcylation of multiple proteins inhibits viral replication and the latent-lytic cycle.