2. Academic Validation
  3. Coronaviral nsp6 hijacks ERAD machinery to facilitate lipolysis and supply membrane components for DMV growth

Coronaviral nsp6 hijacks ERAD machinery to facilitate lipolysis and supply membrane components for DMV growth

  • Nat Commun. 2025 Nov 18;16(1):10094. doi: 10.1038/s41467-025-65118-y.
Shu-Rui Liu # 1 2 3,  Yuzheng Zhou # 4,  Jinwei Li 3,  Zhaohuan Wang 2,  Yu Ye 5,  Jiafan Miao 5,  Keda Shi 3,  Birong Zheng 1 2,  Binbin Ding 2 3,  Jian Pan 5,  Chun-Mei Li 5,  Yiping Li 1,  Panpan Hou 6,  Deyin Guo 7 8 9
Affiliations

Affiliations

  • 1 Key Laboratory of Tropical Disease Control of Ministry of Education, Institute of Human Virology, Department of Pathogen Biology and Biosecurity, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong, China.
  • 2 Guangzhou National Laboratory, Guangzhou International Bio-Island, Guangzhou, China.
  • 3 State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China.
  • 4 Institute for Hepatology, National Clinical Research Center for Infectious Disease, Shenzhen Third People's Hospital, The Second Affiliated Hospital, School of Medicine, Southern University of Science and Technology, Shenzhen, China.
  • 5 Centre for Infection and Immunity Study (CIIS), School of Medicine, Shenzhen Campus of Sun Yat-Sen University, Shenzhen, Guangdong, China.
  • 6 State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China. [email protected].
  • 7 Key Laboratory of Tropical Disease Control of Ministry of Education, Institute of Human Virology, Department of Pathogen Biology and Biosecurity, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong, China. [email protected].
  • 8 Guangzhou National Laboratory, Guangzhou International Bio-Island, Guangzhou, China. [email protected].
  • 9 State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China. [email protected].
  • # Contributed equally.
PMID: 41253842 DOI: 10.1038/s41467-025-65118-y
Abstract

The positive-strand RNA ( + RNA) viruses extensively remodel cellular endomembranes to facilitate viral replication, with coronaviruses forming a specialized viral replication organelle (RO) known as double-membrane vesicles (DMVs). These DMVs serve as platforms for viral replication and shield viral RNA from host immune recognition. However, the biogenesis, structural organization, and physiological properties of DMVs remain poorly understood. In this study, we demonstrate that the coronavirus non-structural protein 6 (nsp6) anchors DMVs to lipid droplets (LDs), hijacks the endoplasmic reticulum (ER)-associated protein degradation (ERAD) machinery to degrade PLIN2, and redirects fatty acids (FAs) from LDs to DMVs, thereby supplying lipids for DMV growth. Furthermore, nsp6 anchors ERAD-derived vesicles to DMVs, directly refurnishing membrane components for DMV expansion. Disruption of lipolysis or ERAD impairs DMV formation and inhibits coronaviral replication. We further validated the Antiviral effects of ERAD inhibition in female mice in vivo. Our findings elucidate the mechanisms and functional significance of virus-induced organelle remodeling and DMV biogenesis. Given the conservation of viral ROs across +RNA viruses, these structures represent a promising and attractive target for the development of broad-spectrum Antiviral therapies.

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