Article ; Online: 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.
2023 Volume 15, Issue 2
Abstract: 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) ...
| Abstract | 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'. 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' 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' into a new C-terminal fragment (S2″), leading to reduced cell-to-cell fusion. Indeed, S-mutants that increase S2″ formation abolished S2' and cell-to-cell fusion, as well as pseudoparticle entry, indicating that the formation of S2″ 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. |
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| MeSH term(s) | Humans ; Angiotensin-Converting Enzyme 2 ; Cell Fusion ; COVID-19 ; HeLa Cells ; Metalloproteases ; Proprotein Convertase 9/genetics ; SARS-CoV-2 ; Sterol Regulatory Element Binding Protein 1 |
| Chemical Substances | Angiotensin-Converting Enzyme 2 (EC 3.4.17.23) ; Metalloproteases (EC 3.4.-) ; PCSK9 protein, human (EC 3.4.21.-) ; Proprotein Convertase 9 (EC 3.4.21.-) ; Sterol Regulatory Element Binding Protein 1 ; membrane-bound transcription factor peptidase, site 1 (EC 3.4.21.112) |
| Language | English |
| Publishing date | 2023-01-27 |
| Publishing country | Switzerland |
| Document type | Journal Article ; Research Support, Non-U.S. Gov't |
| ZDB-ID | 2516098-9 |
| ISSN | 1999-4915 ; 1999-4915 |
| ISSN (online) | 1999-4915 |
| ISSN | 1999-4915 |
| DOI | 10.3390/v15020360 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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