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

Overview

Journal Cell

Publisher Cell Press

Specialty Cell Biology

Date 2020 Nov 6

PMID 33157038

Citations 327

Authors

Sourish Ghosh

Teegan A Dellibovi-Ragheb

Adeline Kerviel

Eowyn Pak

Qi Qiu

Matthew Fisher

Peter M Takvorian

Christopher Bleck

Victor W Hsu

Anthony R Fehr

Stanley Perlman

Sooraj R Achar

Marco R Straus

Gary R Whittaker

Cornelis A M de Haan

John Kehrl

Gregoire Altan-Bonnet

Nihal Altan-Bonnet

Affiliations

Soon will be listed here.

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.

Citing Articles

Subcellular localization of SARS-CoV-2 E and 3a proteins along the secretory pathway.

Hinkle J, Trychta K, Wires E, Osborn R, Leach J, Faraz Z J Mol Histol. 2025; 56(2):98.

PMID: 40025386 PMC: 11872775. DOI: 10.1007/s10735-025-10375-w.

A Comparison of Conserved Features in the Human Coronavirus Family Shows That Studies of Viruses Less Pathogenic than SARS-CoV-2, Such as HCoV-OC43, Are Good Model Systems for Elucidating Basic Mechanisms of Infection and Replication in Standard....

Heffner A, Rouault T Viruses. 2025; 17(2).

PMID: 40007010 PMC: 11860170. DOI: 10.3390/v17020256.

Inhaled Dry Powder of Antiviral Agents: A Promising Approach to Treating Respiratory Viral Pathogens.

Saha T, Masum Z, Biswas A, Mou M, Ahmed S, Saha T Viruses. 2025; 17(2).

PMID: 40007007 PMC: 11860668. DOI: 10.3390/v17020252.

In Vitro Evaluation of Aryl Hydrocarbon Receptor Involvement in Feline Coronavirus Infection.

Del Sorbo L, Giugliano R, Cerracchio C, Iovane V, Salvatore M, Serra F Viruses. 2025; 17(2).

PMID: 40006982 PMC: 11860311. DOI: 10.3390/v17020227.

ARF4-mediated intracellular transport as a broad-spectrum antiviral target.

Li M, Deng K, Cheng X, Siu L, Gao Z, Naik T Nat Microbiol. 2025; 10(3):710-723.

PMID: 39972062 DOI: 10.1038/s41564-025-01940-w.

References

Channappanavar R, Fehr A, Vijay R, Mack M, Zhao J, Meyerholz D . Dysregulated Type I Interferon and Inflammatory Monocyte-Macrophage Responses Cause Lethal Pneumonia in SARS-CoV-Infected Mice. Cell Host Microbe. 2016; 19(2):181-93. PMC: 4752723. DOI: 10.1016/j.chom.2016.01.007. View

de Haan C, Kuo L, Masters P, Vennema H, Rottier P . Coronavirus particle assembly: primary structure requirements of the membrane protein. J Virol. 1998; 72(8):6838-50. PMC: 109893. DOI: 10.1128/JVI.72.8.6838-6850.1998. View

Machamer C . Accommodation of large cargo within Golgi cisternae. Histochem Cell Biol. 2013; 140(3):261-9. PMC: 3756474. DOI: 10.1007/s00418-013-1120-y. View

Chen Y, Du W, Hagemeijer M, Takvorian P, Pau C, Cali A . Phosphatidylserine vesicles enable efficient en bloc transmission of enteroviruses. Cell. 2015; 160(4):619-630. PMC: 6704014. DOI: 10.1016/j.cell.2015.01.032. View

Samarel A, Ferguson A, Decker R, Lesch M . Effects of cysteine protease inhibitors on rabbit cathepsin D maturation. Am J Physiol. 1989; 257(6 Pt 1):C1069-79. DOI: 10.1152/ajpcell.1989.257.6.C1069. View

Ravindran M, Bagchi P, Cunningham C, Tsai B . Opportunistic intruders: how viruses orchestrate ER functions to infect cells. Nat Rev Microbiol. 2016; 14(7):407-420. PMC: 5272919. DOI: 10.1038/nrmicro.2016.60. View

Ballabio A, Bonifacino J . Lysosomes as dynamic regulators of cell and organismal homeostasis. Nat Rev Mol Cell Biol. 2019; 21(2):101-118. DOI: 10.1038/s41580-019-0185-4. View

Puelles V, Lutgehetmann M, Lindenmeyer M, Sperhake J, Wong M, Allweiss L . Multiorgan and Renal Tropism of SARS-CoV-2. N Engl J Med. 2020; 383(6):590-592. PMC: 7240771. DOI: 10.1056/NEJMc2011400. View

Lu R, Zhao X, Li J, Niu P, Yang B, Wu H . Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding. Lancet. 2020; 395(10224):565-574. PMC: 7159086. DOI: 10.1016/S0140-6736(20)30251-8. View

10.

Strous G, van Kerkhof P, van Meer G, Rijnboutt S, Stoorvogel W . Differential effects of brefeldin A on transport of secretory and lysosomal proteins. J Biol Chem. 1993; 268(4):2341-7. View

11.

Martin M, Gao X, Lee J, Nelson G, Detels R, Goedert J . Epistatic interaction between KIR3DS1 and HLA-B delays the progression to AIDS. Nat Genet. 2002; 31(4):429-34. DOI: 10.1038/ng934. View

12.

Humphries 4th W, Payne C . Imaging lysosomal enzyme activity in live cells using self-quenched substrates. Anal Biochem. 2012; 424(2):178-83. PMC: 3327787. DOI: 10.1016/j.ab.2012.02.033. View

13.

Ruch T, Machamer C . The coronavirus E protein: assembly and beyond. Viruses. 2012; 4(3):363-82. PMC: 3347032. DOI: 10.3390/v4030363. View

14.

Vanlandingham P, Ceresa B . Rab7 regulates late endocytic trafficking downstream of multivesicular body biogenesis and cargo sequestration. J Biol Chem. 2009; 284(18):12110-24. PMC: 2673280. DOI: 10.1074/jbc.M809277200. View

15.

Lippincott-Schwartz J, Yuan L, Bonifacino J, Klausner R . Rapid redistribution of Golgi proteins into the ER in cells treated with brefeldin A: evidence for membrane cycling from Golgi to ER. Cell. 1989; 56(5):801-13. PMC: 7173269. DOI: 10.1016/0092-8674(89)90685-5. View

16.

Martinez I, Chakrabarti S, Hellevik T, MOREHEAD J, Fowler K, Andrews N . Synaptotagmin VII regulates Ca(2+)-dependent exocytosis of lysosomes in fibroblasts. J Cell Biol. 2000; 148(6):1141-49. PMC: 2174306. DOI: 10.1083/jcb.148.6.1141. View

17.

Boda A, Lorincz P, Takats S, Csizmadia T, Toth S, Kovacs A . Drosophila Arl8 is a general positive regulator of lysosomal fusion events. Biochim Biophys Acta Mol Cell Res. 2018; 1866(4):533-544. DOI: 10.1016/j.bbamcr.2018.12.011. View

18.

Leibowitz J, Kaufman G, Liu P . Coronaviruses: propagation, quantification, storage, and construction of recombinant mouse hepatitis virus. Curr Protoc Microbiol. 2011; Chapter 15:Unit 15E.1. PMC: 3119930. DOI: 10.1002/9780471729259.mc15e01s21. View

19.

Long Q, Tang X, Shi Q, Li Q, Deng H, Yuan J . Clinical and immunological assessment of asymptomatic SARS-CoV-2 infections. Nat Med. 2020; 26(8):1200-1204. DOI: 10.1038/s41591-020-0965-6. View

20.

Munro S, Pelham H . A C-terminal signal prevents secretion of luminal ER proteins. Cell. 1987; 48(5):899-907. DOI: 10.1016/0092-8674(87)90086-9. View