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

{ 'indexed': {'date-parts': [[2024, 3, 7]], 'date-time': '2024-03-07T00:35:17Z', 'timestamp': 1709771717696}, 'reference-count': 63, 'publisher': 'Springer Science and Business Media LLC', 'issue': '1', 'license': [ { 'start': { 'date-parts': [[2024, 3, 6]], 'date-time': '2024-03-06T00:00:00Z', 'timestamp': 1709683200000}, 'content-version': 'tdm', 'delay-in-days': 0, 'URL': 'https://creativecommons.org/licenses/by/4.0'}, { 'start': { 'date-parts': [[2024, 3, 6]], 'date-time': '2024-03-06T00:00:00Z', 'timestamp': 1709683200000}, 'content-version': 'vor', 'delay-in-days': 0, 'URL': 'https://creativecommons.org/licenses/by/4.0'}], 'funder': [ { 'DOI': '10.13039/501100001843', 'name': 'DST | Science and Engineering Research Board', 'doi-asserted-by': 'publisher', 'award': ['CRG/2022/003266', 'CVD/2020/000733', 'IPA/2020/000168']}, { 'DOI': '10.13039/501100009053', 'name': 'DBT India Alliance', 'doi-asserted-by': 'publisher', 'award': ['IA/I/14/2/501543', 'IA/S/19/1/504270']}, { 'DOI': '10.13039/501100001407', 'name': 'Department of Biotechnology, Ministry of Science and Technology', 'doi-asserted-by': 'publisher', 'award': ['BT/HRD/NWBA/39/01/2018-19']}], 'content-domain': {'domain': ['link.springer.com'], 'crossmark-restriction': False}, 'abstract': '<jats:title>Abstract</jats:title><jats:p>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.</jats:p>', 'DOI': '10.1038/s41467-024-46417-2', 'type': 'journal-article', 'created': {'date-parts': [[2024, 3, 6]], 'date-time': '2024-03-06T18:02:49Z', 'timestamp': 1709748169000}, 'update-policy': 'http://dx.doi.org/10.1007/springer_crossmark_policy', 'source': 'Crossref', 'is-referenced-by-count': 0, 'title': 'SARS-CoV-2 virulence factor ORF3a blocks lysosome function by modulating TBC1D5-dependent Rab7 ' 'GTPase cycle', 'prefix': '10.1038', 'volume': '15', 'author': [ {'given': 'Kshitiz', 'family': 'Walia', 'sequence': 'first', 'affiliation': []}, {'given': 'Abhishek', 'family': 'Sharma', 'sequence': 'additional', 'affiliation': []}, {'given': 'Sankalita', 'family': 'Paul', 'sequence': 'additional', 'affiliation': []}, {'given': 'Priya', 'family': 'Chouhan', 'sequence': 'additional', 'affiliation': []}, { 'ORCID': 'http://orcid.org/0000-0001-9614-1032', 'authenticated-orcid': False, 'given': 'Gaurav', 'family': 'Kumar', 'sequence': 'additional', 'affiliation': []}, {'given': 'Rajesh', 'family': 'Ringe', 'sequence': 'additional', 'affiliation': []}, { 'ORCID': 'http://orcid.org/0000-0002-4117-4790', 'authenticated-orcid': False, 'given': 'Mahak', 'family': 'Sharma', 'sequence': 'additional', 'affiliation': []}, { 'ORCID': 'http://orcid.org/0000-0001-5476-4127', 'authenticated-orcid': False, 'given': 'Amit', 'family': 'Tuli', 'sequence': 'additional', 'affiliation': []}], 'member': '297', 'published-online': {'date-parts': [[2024, 3, 6]]}, 'reference': [ { 'key': '46417_CR1', 'doi-asserted-by': 'publisher', 'first-page': '82', 'DOI': '10.1016/j.mib.2016.05.003', 'volume': '32', 'author': 'A Shulla', 'year': '2016', 'unstructured': 'Shulla, A. & Randall, G. 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