β-Coronaviruses Use Lysosomes for Egress Instead of the Biosynthetic Secretory Pathway

  • Cell. 2020 Dec 10;183(6):1520-1535.e14. doi: 10.1016/j.cell.2020.10.039.
Sourish Ghosh  1 ,  Teegan A Dellibovi-Ragheb  1 ,  Adeline Kerviel  1 ,  Eowyn Pak  1 ,  Qi Qiu  1 ,  Matthew Fisher  1 ,  Peter M Takvorian  2 ,  Christopher Bleck  3 ,  Victor W Hsu  4 ,  Anthony R Fehr  5 ,  Stanley Perlman  5 ,  Sooraj R Achar  6 ,  Marco R Straus  7 ,  Gary R Whittaker  7 ,  Cornelis A M de Haan  8 ,  John Kehrl  9 ,  Grégoire Altan-Bonnet  10 ,  Nihal Altan-Bonnet  11
Affiliations
  • 1. Laboratory of Host-Pathogen Dynamics, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
  • 2. Federated Department of Biological Sciences, Rutgers-State University of New Jersey, Newark, NJ, USA.
  • 3. Electron Microscopy Core Facility, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
  • 4. Division of Rheumatology, Inflammation and Immunity, Brigham and Women's Hospital, Department of Medicine, Harvard Medical School, Boston, MA, USA.
  • 5. Department of Microbiology and Immunology, University of Iowa, Iowa City, IA, USA.
  • 6. lmmunodynamics Group - Laboratory of Integrative Cancer Immunology, National Cancer Institute, Bethesda, MD, USA.
  • 7. Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA.
  • 8. Department of Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, the Netherlands.
  • 9. B-Cell Molecular Immunology Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
  • 10. lmmunodynamics Group - Laboratory of Integrative Cancer Immunology, National Cancer Institute, Bethesda, MD, USA. Electronic address: [email protected].
  • 11. Laboratory of Host-Pathogen Dynamics, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA. Electronic address: [email protected].
PMID: 33157038 DOI: 10.1016/j.cell.2020.10.039
Abstract

β-Coronaviruses are a family of positive-strand enveloped RNA viruses that includes the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Much is known regarding their cellular entry and replication pathways, but their mode of egress remains uncertain. Using imaging methodologies and virus-specific reporters, we demonstrate that β-coronaviruses utilize lysosomal trafficking for egress rather than the biosynthetic secretory pathway more commonly used by other enveloped viruses. This unconventional egress is regulated by the Arf-like small GTPase Arl8b and can be blocked by the Rab7 GTPase competitive inhibitor CID1067700. Such non-lytic release of β-coronaviruses results in lysosome deacidification, inactivation of lysosomal degradation Enzymes, and disruption of antigen presentation pathways. β-Coronavirus-induced exploitation of lysosomal organelles for egress provides insights into the cellular and immunological abnormalities observed in patients and suggests new therapeutic modalities.

Keywords
CD1067700; Rab7; SARS-CoV-2; acidification/deacidification ARL8b; antigen presentation; coronavirus; lysosome; pH; viral egress; viral immunology.