β-Coronaviruses use lysosomes for egress instead of the biosynthetic secretory pathway

Ghosh, Sourish; Dellibovi-Ragheb, Teegan A.; Kerviel, Adeline; Pak, Eowyn; Qiu, Qi; Fisher, Matthew; Takvorian, Peter M.; Bleck, Christopher; Hsu, Victor; Fehr, Anthony R.; Perlman, Stanley; Achar, Souraj R.; Straus, Marco R.; Whittaker, Gary R.; de Haan, Cornelis A.M.; Kehrl, John; Altan-Bonnet, Gregoire; Altan-Bonnet, Nihal

β-Coronaviruses are a family of positive-strand enveloped RNA viruses that include the severe acute respiratory syndrome-CoV2 (SARS-CoV2). 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-Coronavirus results in lysosome deacidification, inactivation of lysosomal degradation enzymes and disruption of antigen presentation pathways. The 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.