O-GlcNAcylation: A Nutrient-Sensitive Metabolic Rheostat in Antiviral Immunity and Viral Pathogenesis
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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.
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This Zenodo record is a permanently preserved version of a PREreview. You can view the complete PREreview at https://prereview.org/reviews/19423635.
Write a short summary of the research's main findings and how this work has moved the field forward.
Major issues
While the review provides a strong overview of the HBP–O-GlcNAc axis in antiviral immunity, it lacks detailed mechanistic validation.
Key experimental approaches such as site-directed mutagenesis (e.g., S198A/S198D) are not discussed.
Metabolic perturbations like glucose deprivation or 2-DG treatment are also absent. Additionally, AMPK activation and its effect on phase separation are not addressed.
The review does not explore protein–protein interactions such as Co-IP with eIF3b. Emerging concepts like YTHDF1 phase separation dynamics are underrepresented despite their relevance.
This Zenodo record is a permanently preserved version of a PREreview. You can view the complete PREreview at https://prereview.org/reviews/19423635.
Write a short summary of the research's main findings and how this work has moved the field forward.
Major issues
While the review provides a strong overview of the HBP–O-GlcNAc axis in antiviral immunity, it lacks detailed mechanistic validation.
Key experimental approaches such as site-directed mutagenesis (e.g., S198A/S198D) are not discussed.
Metabolic perturbations like glucose deprivation or 2-DG treatment are also absent. Additionally, AMPK activation and its effect on phase separation are not addressed.
The review does not explore protein–protein interactions such as Co-IP with eIF3b. Emerging concepts like YTHDF1 phase separation dynamics are underrepresented despite their relevance.
Minor issues
While the review provides a strong conceptual overview of the HBP–O-GlcNAc axis, it lacks quantitative visualization
No charts or data-driven figures are included to support or summarize key findings.
Competing interests
The author declares that they have no competing interests.
Use of Artificial Intelligence (AI)
The author declares that they used generative AI to come up with new ideas for their review.
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