2. Academic Validation
  3. ORF3a of the COVID-19 virus SARS-CoV-2 blocks HOPS complex-mediated assembly of the SNARE complex required for autolysosome formation

ORF3a of the COVID-19 virus SARS-CoV-2 blocks HOPS complex-mediated assembly of the SNARE complex required for autolysosome formation

  • Dev Cell. 2021 Feb 22;56(4):427-442.e5. doi: 10.1016/j.devcel.2020.12.010.
Guangyan Miao 1,  Hongyu Zhao 1,  Yan Li 2,  Mingming Ji 1,  Yong Chen 1,  Yi Shi 2,  Yuhai Bi 2,  Peihui Wang 3,  Hong Zhang 4
Affiliations

Affiliations

  • 1 National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, P.R. China.
  • 2 CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, P.R. China.
  • 3 Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University, Ji'nan, Shandong 250012, P.R. China.
  • 4 National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, P.R. China; College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, P.R. China. Electronic address: hongzhang@ibp.ac.cn.
PMID: 33422265 DOI: 10.1016/j.devcel.2020.12.010
Abstract

Autophagy acts as a cellular surveillance mechanism to combat invading pathogens. Viruses have evolved various strategies to block Autophagy and even subvert it for their replication and release. Here, we demonstrated that ORF3a of the COVID-19 virus SARS-CoV-2 inhibits Autophagy activity by blocking fusion of autophagosomes/amphisomes with lysosomes. The late endosome-localized ORF3a directly interacts with and sequestrates the homotypic fusion and protein sorting (HOPS) component VPS39, thereby preventing HOPS complex from interacting with the autophagosomal SNARE protein STX17. This blocks assembly of the STX17-SNAP29-VAMP8 SNARE complex, which mediates autophagosome/amphisome fusion with lysosomes. Expression of ORF3a also damages lysosomes and impairs their function. SARS-CoV-2 virus Infection blocks Autophagy, resulting in accumulation of autophagosomes/amphisomes, and causes late endosomal sequestration of VPS39. Surprisingly, ORF3a from the SARS virus SARS-CoV fails to interact with HOPS or block Autophagy. Our study reveals a mechanism by which SARS-CoV-2 evades lysosomal destruction and provides insights for developing new strategies to treat COVID-19.

Keywords

COVID-19; DMV; HOPS; ORF3a; SARS-CoV-2; SNARE; autophagy.

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