Interferon-stimulated gene GALNT2 restricts respiratory virus infections
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<sup>-/-</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 (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.
Authors
- Jung-Eun Park (ORCID: https://orcid.org/0000-0002-0423-6147)
- Jianfen Zhuo (ORCID: https://orcid.org/0000-0002-0177-3596)
- Yanqiu Yuan (ORCID: https://orcid.org/0000-0001-8360-4843)
- Zhen Zhuang (ORCID: https://orcid.org/0000-0001-8658-1077)
- Kaixin Zhou (ORCID: https://orcid.org/0000-0002-4751-7248)
- Jincun Zhao (ORCID: https://orcid.org/0000-0003-2515-5589)
- Lu Zhang (ORCID: https://orcid.org/0000-0003-1606-8619)
- Yanying Yu (ORCID: https://orcid.org/0000-0002-2247-5782)
- Hongyu Zhao (ORCID: https://orcid.org/0000-0003-1477-5731)
- Huina Hu
- Wei Cheng (ORCID: https://orcid.org/0000-0002-1475-4079)
- Qingtao Hu (ORCID: https://orcid.org/0000-0002-8291-7116)
- Donglan Liu (ORCID: https://orcid.org/0000-0002-8342-7637)
- Stanley Perlman (ORCID: https://orcid.org/0000-0003-4213-2354)
- Yang Mao (ORCID: https://orcid.org/0000-0002-9674-1158)
- Wenxuan Tang (ORCID: https://orcid.org/0009-0000-2816-7089)
- Ruangang Pan (ORCID: https://orcid.org/0000-0002-9336-9717)
- Ran Wei (ORCID: https://orcid.org/0000-0002-0586-9560)
- Jun Dai (ORCID: https://orcid.org/0000-0001-5461-4786)
- Yonghao Xu (ORCID: https://orcid.org/0000-0002-4905-0979)
- Yanqun Wang (ORCID: https://orcid.org/0000-0003-4676-2812)
- Rong Bai
- Shengjun Wang (ORCID: https://orcid.org/0000-0002-8044-7018)
- Jingxian Zhao (ORCID: https://orcid.org/0000-0002-2615-3182)
- Airu Zhu (ORCID: https://orcid.org/0000-0002-6374-4467)
- Qiang Ding (ORCID: https://orcid.org/0000-0002-6226-869X)
- Chen Zhao (ORCID: https://orcid.org/0000-0001-7143-9764)
- Yuqi He (ORCID: https://orcid.org/0000-0001-5972-5477)
- Qiuhui Zeng
- Qihong Yan (ORCID: https://orcid.org/0000-0003-1645-8764)
- Fang Li (ORCID: https://orcid.org/0000-0002-7109-2032)
- Yu Shi (ORCID: https://orcid.org/0000-0003-0651-4769)
- Na Li (ORCID: https://orcid.org/0000-0003-0114-4877)
- Tao Wang (ORCID: https://orcid.org/0000-0002-2677-312X)
- Jinghong Yang (ORCID: https://orcid.org/0009-0008-5867-5613)
- Yiliang Wang (ORCID: https://orcid.org/0000-0002-0650-5662)
- Fenghua Chen (ORCID: https://orcid.org/0000-0002-4462-0880)
- Shaobo Wang (ORCID: https://orcid.org/0000-0003-0481-707X)
- Jing Sun (ORCID: https://orcid.org/0000-0003-4440-4704)
- Yuzheng Zhou (ORCID: https://orcid.org/0000-0003-3804-6752)
- Lingyu Sun
- Hua Tao (ORCID: https://orcid.org/0009-0009-8987-0523)
- Kuai Yu (ORCID: https://orcid.org/0000-0001-9699-4780)
- Pengfei Li
- Dong Wang (ORCID: https://orcid.org/0000-0003-4415-1102)
Institutions
- University of Iowa (US)
- Sun Yat-sen University (CN)
- Chungnam National University (KR)
- Southern University of Science and Technology (CN)
- ShanghaiTech University (CN)
- Ji Hua Laboratory (CN)
- Guangzhou Experimental Station (CN)
- First Affiliated Hospital of Guangzhou Medical University (CN)
- Guangzhou Regenerative Medicine and Health Guangdong Laboratory (CN)
- TCM-Intigrated Cancer Center of Southern Medical University (CN)
- State Key Laboratory of Respiratory Disease (CN)
- Shenzhen Third People’s Hospital (CN)
- Guangzhou Medical University (CN)
- Tsinghua University (CN)
Publication Details
- Journal
- Nature Microbiology
- Published
- 2025-12-12
- DOI
- https://doi.org/10.1038/s41564-025-02200-7
- Citations
- 1
- Primary Topic
- SARS-CoV-2 and COVID-19 Research
- Type
- article
- Field-Weighted Citation Impact
- 1.40