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

Author

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  • Shu-Rui Liu

    (Sun Yat-Sen University
    Guangzhou International Bio-Island
    the First Affiliated Hospital of Guangzhou Medical University)

  • Yuzheng Zhou

    (Southern University of Science and Technology)

  • Jinwei Li

    (the First Affiliated Hospital of Guangzhou Medical University)

  • Zhaohuan Wang

    (Guangzhou International Bio-Island)

  • Yu Ye

    (Shenzhen Campus of Sun Yat-Sen University)

  • Jiafan Miao

    (Shenzhen Campus of Sun Yat-Sen University)

  • Keda Shi

    (the First Affiliated Hospital of Guangzhou Medical University)

  • Birong Zheng

    (Sun Yat-Sen University
    Guangzhou International Bio-Island)

  • Binbin Ding

    (Guangzhou International Bio-Island
    the First Affiliated Hospital of Guangzhou Medical University)

  • Jian Pan

    (Shenzhen Campus of Sun Yat-Sen University)

  • Chun-Mei Li

    (Shenzhen Campus of Sun Yat-Sen University)

  • Yiping Li

    (Sun Yat-Sen University)

  • Panpan Hou

    (the First Affiliated Hospital of Guangzhou Medical University)

  • Deyin Guo

    (Sun Yat-Sen University
    Guangzhou International Bio-Island
    the First Affiliated Hospital of Guangzhou Medical University)

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.

Suggested Citation

  • Shu-Rui Liu & Yuzheng Zhou & Jinwei Li & Zhaohuan Wang & Yu Ye & Jiafan Miao & Keda Shi & Birong Zheng & Binbin Ding & Jian Pan & Chun-Mei Li & Yiping Li & Panpan Hou & Deyin Guo, 2025. "Coronaviral nsp6 hijacks ERAD machinery to facilitate lipolysis and supply membrane components for DMV growth," Nature Communications, Nature, vol. 16(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-65118-y
    DOI: 10.1038/s41467-025-65118-y
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