{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T05:04:15Z","timestamp":1784869455905,"version":"3.55.0"},"reference-count":102,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2023,1,27]],"date-time":"2023-01-27T00:00:00Z","timestamp":1674777600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"CIHR Foundation","award":["148363"],"award-info":[{"award-number":["148363"]}]},{"name":"CIHR Foundation","award":["154324"],"award-info":[{"award-number":["154324"]}]},{"name":"CIHR Foundation","award":["950-231335"],"award-info":[{"award-number":["950-231335"]}]},{"name":"CIHR Foundation","award":["HAL 157986"],"award-info":[{"award-number":["HAL 157986"]}]},{"name":"Canada Research Chairs in Precursor Proteolysis","award":["148363"],"award-info":[{"award-number":["148363"]}]},{"name":"Canada Research Chairs in Precursor Proteolysis","award":["154324"],"award-info":[{"award-number":["154324"]}]},{"name":"Canada Research Chairs in Precursor Proteolysis","award":["950-231335"],"award-info":[{"award-number":["950-231335"]}]},{"name":"Canada Research Chairs in Precursor Proteolysis","award":["HAL 157986"],"award-info":[{"award-number":["HAL 157986"]}]},{"name":"CIHR CHAMPS Team","award":["148363"],"award-info":[{"award-number":["148363"]}]},{"name":"CIHR CHAMPS Team","award":["154324"],"award-info":[{"award-number":["154324"]}]},{"name":"CIHR CHAMPS Team","award":["950-231335"],"award-info":[{"award-number":["950-231335"]}]},{"name":"CIHR CHAMPS Team","award":["HAL 157986"],"award-info":[{"award-number":["HAL 157986"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Proprotein convertases activate various envelope glycoproteins and participate in cellular entry of many viruses. We recently showed that the convertase furin is critical for the infectivity of SARS-CoV-2, which requires cleavage of its spike protein (S) at two sites: S1\/S2 and S2\u2032. This study investigates the implication of the two cholesterol-regulating convertases SKI-1 and PCSK9 in SARS-CoV-2 entry. The assays used were cell-to-cell fusion in HeLa cells and pseudoparticle entry into Calu-3 cells. SKI-1 increased cell-to-cell fusion by enhancing the activation of SREBP-2, whereas PCSK9 reduced cell-to-cell fusion by promoting the cellular degradation of ACE2. SKI-1 activity led to enhanced S2\u2032 formation, which was attributed to increased metalloprotease activity as a response to enhanced cholesterol levels via activated SREBP-2. However, high metalloprotease activity resulted in the shedding of S2\u2032 into a new C-terminal fragment (S2\u2033), leading to reduced cell-to-cell fusion. Indeed, S-mutants that increase S2\u2033 formation abolished S2\u2032 and cell-to-cell fusion, as well as pseudoparticle entry, indicating that the formation of S2\u2033 prevents SARS-CoV-2 cell-to-cell fusion and entry. We next demonstrated that PCSK9 enhanced the cellular degradation of ACE2, thereby reducing cell-to-cell fusion. However, different from the LDLR, a canonical target of PCSK9, the C-terminal CHRD domain of PCSK9 is dispensable for the PCSK9-induced degradation of ACE2. Molecular modeling suggested the binding of ACE2 to the Pro\/Catalytic domains of mature PCSK9. Thus, both cholesterol-regulating convertases SKI-1 and PCSK9 can modulate SARS-CoV-2 entry via two independent mechanisms.<\/jats:p>","DOI":"10.3390\/v15020360","type":"journal-article","created":{"date-parts":[[2023,1,30]],"date-time":"2023-01-30T07:34:41Z","timestamp":1675064081000},"page":"360","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["SKI-1\/S1P Facilitates SARS-CoV-2 Spike Induced Cell-to-Cell Fusion via Activation of SREBP-2 and Metalloproteases, Whereas PCSK9 Enhances the Degradation of ACE2"],"prefix":"10.3390","volume":"15","author":[{"given":"Rachid","family":"Essalmani","sequence":"first","affiliation":[{"name":"Laboratory of Biochemical Neuroendocrinology, Montreal Clinical Research Institute (IRCM), Universit\u00e9 de Montr\u00e9al, Montreal, QC H2W 1R7, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ursula","family":"Andr\u00e9o","sequence":"additional","affiliation":[{"name":"Laboratory of Biochemical Neuroendocrinology, Montreal Clinical Research Institute (IRCM), Universit\u00e9 de Montr\u00e9al, Montreal, QC H2W 1R7, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra","family":"Evagelidis","sequence":"additional","affiliation":[{"name":"Laboratory of Biochemical Neuroendocrinology, Montreal Clinical Research Institute (IRCM), Universit\u00e9 de Montr\u00e9al, Montreal, QC H2W 1R7, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ma\u00eflys","family":"Le D\u00e9v\u00e9hat","sequence":"additional","affiliation":[{"name":"Laboratory of Biochemical Neuroendocrinology, Montreal Clinical Research Institute (IRCM), Universit\u00e9 de Montr\u00e9al, Montreal, QC H2W 1R7, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oscar Henrique","family":"Pereira Ramos","sequence":"additional","affiliation":[{"name":"D\u00e9partement M\u00e9dicaments et Technologies pour la Sant\u00e9 (DMTS), Universit\u00e9 Paris-Saclay, CEA, INRAE, SI-MoS, 91191 Gif-sur-Yvette, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3149-4774","authenticated-orcid":false,"given":"Carole","family":"Fruchart Gaillard","sequence":"additional","affiliation":[{"name":"D\u00e9partement M\u00e9dicaments et Technologies pour la Sant\u00e9 (DMTS), Universit\u00e9 Paris-Saclay, CEA, INRAE, SI-MoS, 91191 Gif-sur-Yvette, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Delia","family":"Susan-Resiga","sequence":"additional","affiliation":[{"name":"Laboratory of Biochemical Neuroendocrinology, Montreal Clinical Research Institute (IRCM), Universit\u00e9 de Montr\u00e9al, Montreal, QC H2W 1R7, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1269-3791","authenticated-orcid":false,"given":"\u00c9ric A.","family":"Cohen","sequence":"additional","affiliation":[{"name":"Laboratory of Human Retrovirology, Montreal Clinical Research Institute (IRCM), Universit\u00e9 de Montr\u00e9al, 110 Pine Ave West, Montreal, QC H2W 1R7, Canada"},{"name":"Department of Microbiology, Infectiology and Immunology, Universit\u00e9 de Montr\u00e9al, Montreal, QC H3C 3J7, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6503-9342","authenticated-orcid":false,"given":"Nabil G.","family":"Seidah","sequence":"additional","affiliation":[{"name":"Laboratory of Biochemical Neuroendocrinology, Montreal Clinical Research Institute (IRCM), Universit\u00e9 de Montr\u00e9al, Montreal, QC H2W 1R7, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,1,27]]},"reference":[{"key":"ref_1","first-page":"1196","article-title":"COVID-19 and its genomic variants: Molecular pathogenesis and therapeutic interventions","volume":"21","author":"Manna","year":"2022","journal-title":"EXCLI J."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"105507","DOI":"10.1016\/j.isci.2022.105507","article-title":"Enhanced virulence and waning vaccine-elicited antibodies account for breakthrough infections caused by SARS-CoV-2 delta and beyond","volume":"25","author":"Kwon","year":"2022","journal-title":"iScience"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"104742","DOI":"10.1016\/j.antiviral.2020.104742","article-title":"The spike glycoprotein of the new coronavirus 2019-nCoV contains a furin-like cleavage site absent in CoV of the same clade","volume":"176","author":"Coutard","year":"2020","journal-title":"Antivir. 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