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Interferon-stimulated gene GALNT2 restricts respiratory virus infections
Journal article   Open access   Peer reviewed

Interferon-stimulated gene GALNT2 restricts respiratory virus infections

Wei Ran, Jinghong Yang, Shi Yu, Qingtao Hu, Yuqi He, Shengjun Wang, Cheng Wei, Jing Sun, Airu Zhu, Fang Li, …
Nature microbiology, Vol.11(1), pp.256-270
01/2026
DOI: 10.1038/s41564-025-02200-7
PMCID: PMC12768973
PMID: 41387548
url
https://doi.org/10.1038/s41564-025-02200-7View
Published (Version of record) Open Access

Abstract

The innate immune response involves interferons (IFNs), antiviral cytokines that upregulate numerous IFN-stimulated genes, many of which have uncharacterized functions and mechanisms. Here we performed transcriptomic profiling of lung tissues from wild-type and IFNAR mice infected with SARS-CoV-2 and single-cell RNA sequencing of bronchoalveolar lavage fluid and peripheral blood mononuclear cells from patients with COVID-19. We identified O-GalNAc transferase 2 (GALNT2), an N-acetylgalactosaminyltransferase, as an antiviral IFN-stimulated gene restricting the replication of multiple coronaviruses and influenza A viruses in vitro and in vivo, contributing to viral clearance and reducing disease severity. Mechanistically, GALNT2-dependent O-linked glycosylation may regulate viral glycoprotein proteolytic processing and impair viral growth by blocking virus-cell fusion. In addition, we found that serine residues at 810/813 in the viral spike protein undergo O-glycosylation and function as the primary genetic determinants of sensitivity or evasion towards GALNT2. Human genetic data analysis revealed that individuals with GALNT2 variants that lost antiviral function had elevated risk of hospitalization following SARS-CoV-2 infection. This study establishes GALNT2 as an antiviral factor against some respiratory virus infections.

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