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<p>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 <i>IFNAR</i><sup>−<i>/</i>−</sup> 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 (<i>GALNT2</i>), 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 <i>GALNT2</i> variants that lost antiviral function had elevated risk of hospitalization following SARS-CoV-2 infection. This study establishes <i>GALNT2</i> as an antiviral factor against some respiratory virus infections.</p>

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Interferon-stimulated gene GALNT2 restricts respiratory virus infections

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月12日

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  • Wei Ran,
  • Jinghong Yang,
  • Shi Yu,
  • Qingtao Hu,
  • Yuqi He,
  • Shengjun Wang,
  • Cheng Wei,
  • Jing Sun,
  • Airu Zhu,
  • Fang Li,
  • Lu Zhang,
  • Pengfei Li,
  • Huina Hu,
  • Ruangang Pan,
  • Yanying Yu,
  • Yanqiu Yuan,
  • Lingyu Sun,
  • Yanqun Wang,
  • Zhaoyong Zhang,
  • Zhao Chen,
  • Donglan Liu,
  • Qihong Yan,
  • Dong Wang,
  • Kuai Yu,
  • Yiliang Wang,
  • Jianfen Zhuo,
  • Zhen Zhuang,
  • Hua Tao,
  • Qiuhui Zeng,
  • Kaixin Zhou,
  • Fenghua Chen,
  • Wenxuan Tang,
  • Yuzheng Zhou,
  • Rong Bai,
  • Yonghao Xu,
  • Na Li,
  • Jun Dai,
  • Hongyu Zhao,
  • Jung-Eun Park,
  • Tao Wang,
  • Qiang Ding,
  • Stanley Perlman,
  • Jingxian Zhao,
  • Yang Mao,
  • Shaobo Wang,
  • Jincun Zhao

摘要

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.