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

DIR@IMTECH: CSIR-Institute of Microbial Technology

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Title SARS-CoV-2 virulence factor ORF3a blocks lysosome function by modulating TBC1D5-dependent Rab7 GTPase cycle
 
Creator Walia, Kshitiz
Sharma, Abhishek
Paul, Sankalita
Chouhan, Priya
Kumar, Gaurav
Ringe, Rajesh
Sharma, Mahak
Tuli, Amit
 
Subject QR Microbiology
 
Description 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.
 
Publisher NATURE
 
Date 2024-03
 
Type Article
PeerReviewed
 
Relation https://www.nature.com/articles/s41467-024-46417-2
http://crdd.osdd.net/open/3125/
 
Identifier Walia, Kshitiz and Sharma, Abhishek and Paul, Sankalita and Chouhan, Priya and Kumar, Gaurav and Ringe, Rajesh and Sharma, Mahak and Tuli, Amit (2024) SARS-CoV-2 virulence factor ORF3a blocks lysosome function by modulating TBC1D5-dependent Rab7 GTPase cycle. NATURE COMMUNICATIONS, 15 (1).