The non-vesicular cholesterol transporter GRAMD1C is a pan-coronavirus antiviral target

  • PLoS Biol. 2026 Apr 6;24(4):e3003736. doi: 10.1371/journal.pbio.3003736.
Zhelin Su  1  2 ,  Zhen Fu  1  2 ,  Yichen Yang  1  2 ,  Yanan Fu  1  2 ,  Jingwen Mo  3 ,  Juan Xu  1  2 ,  Yubei Tan  1  2 ,  Yixin Xiang  1  2 ,  Yuejun Shi  1  2 ,  Shengsong Xie  4 ,  Limeng Sun  1  2 ,  Guiqing Peng  1  2  5
Affiliations
  • 1. State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, Hubei, P. R. China.
  • 2. Key Laboratory of Preventive Veterinary Medicine in Hubei Province, The Cooperative Innovation Center for Sustainable Pig Production, Wuhan, Hubei, P. R. China.
  • 3. University of Science and Technology of China, Hefei, Anhui, P. R. China.
  • 4. Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education & Key Lab of Swine Genetics and Breeding of Ministry of Agriculture and Rural Affairs, Huazhong Agricultural University, Wuhan, Hubei, P. R. China.
  • 5. State Key Laboratory of Agricultural Microbiology, Key Laboratory of Prevention & Control for African Swine Fever and Other Major Pig Diseases, Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, Hubei, P. R. China.
PMID: 41941438 DOI: 10.1371/journal.pbio.3003736
Abstract

Coronaviruses (CoVs) rely heavily on host lipid metabolism for efficient replication, but the specific host pathways involved remain incompletely defined. Here, we identify the non-vesicular Cholesterol transport protein GRAMD1C as a key host factor required for the replication of multiple coronaviruses across α, β, and δ genera, including TGEV, PEDV, HCoV-229E, SARS-CoV-2, MHV, and PDCoV. Mechanistically, GRAMD1C is recruited to the replication factory through its interaction with the viral nonstructural proteins 3 and 4 (nsp3 and nsp4). Transmission electron microscopy (TEM) analysis revealed that GRAMD1C facilitates the formation of replication double-membrane vesicles (DMVs). Further domain rescue and inhibitor experiments demonstrated that GRAMD1C's Cholesterol transport activity is essential for viral replication. Moreover, GRAMD1C-deficient and inhibitor-treated mice exhibited reduced viral replication, underscoring its critical role in vivo. Collectively, our findings expand the current understanding of the importance of non-vesicular Cholesterol transport in viral replication and highlight GRAMD1C as a promising broad-spectrum Antiviral target.

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