SARS-CoV-2 virulence factor ORF3a blocks lysosome function by modulating TBC1D5-dependent Rab7 GTPase cycle

Kshitiz Walia, Abhishek Sharma, Sankalita Paul, Priya Chouhan, Gaurav Kumar, Rajesh Ringe, Mahak Sharma and Amit Tuli ()
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Kshitiz Walia: CSIR-Institute of Microbial Technology (IMTECH)
Abhishek Sharma: CSIR-Institute of Microbial Technology (IMTECH)
Sankalita Paul: Indian Institute of Science Education and Research (IISER)
Priya Chouhan: CSIR-Institute of Microbial Technology (IMTECH)
Gaurav Kumar: CSIR-Institute of Microbial Technology (IMTECH)
Rajesh Ringe: CSIR-Institute of Microbial Technology (IMTECH)
Mahak Sharma: Indian Institute of Science Education and Research (IISER)
Amit Tuli: CSIR-Institute of Microbial Technology (IMTECH)

Nature Communications, 2024, vol. 15, issue 1, 1-24

Abstract: Abstract SARS-CoV-2, the causative agent of COVID-19, uses the host endolysosomal system for entry, replication, and egress. Previous studies have shown that the SARS-CoV-2 virulence factor ORF3a interacts with the lysosomal tethering factor HOPS complex and blocks HOPS-mediated late endosome and autophagosome fusion with lysosomes. Here, we report that SARS-CoV-2 infection leads to hyperactivation of the late endosomal and lysosomal small GTP-binding protein Rab7, which is dependent on ORF3a expression. We also observed Rab7 hyperactivation in naturally occurring ORF3a variants encoded by distinct SARS-CoV-2 variants. We found that ORF3a, in complex with Vps39, sequesters the Rab7 GAP TBC1D5 and displaces Rab7 from this complex. Thus, ORF3a disrupts the GTP hydrolysis cycle of Rab7, which is beneficial for viral production, whereas the Rab7 GDP-locked mutant strongly reduces viral replication. Hyperactivation of Rab7 in ORF3a-expressing cells impaired CI-M6PR retrieval from late endosomes to the trans-Golgi network, disrupting the biosynthetic transport of newly synthesized hydrolases to lysosomes. Furthermore, the tethering of the Rab7- and Arl8b-positive compartments was strikingly reduced upon ORF3a expression. As SARS-CoV-2 egress requires Arl8b, these findings suggest that ORF3a-mediated hyperactivation of Rab7 serves a multitude of functions, including blocking endolysosome formation, interrupting the transport of lysosomal hydrolases, and promoting viral egress.

Date: 2024
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DOI: 10.1038/s41467-024-46417-2

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