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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
Essalmani, R.; Andréo, U.; Evagelidis, A.; Dévéhat, M.L.; Ramos, O.H.P.; Gaillard, C.F.; Susan-Resiga, D.; Cohen, É.A.; Seidah, N.G. 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. Viruses2023, 15, 360.
Essalmani, R.; Andréo, U.; Evagelidis, A.; Dévéhat, M.L.; Ramos, O.H.P.; Gaillard, C.F.; Susan-Resiga, D.; Cohen, É.A.; Seidah, N.G. 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. Viruses 2023, 15, 360.
Essalmani, R.; Andréo, U.; Evagelidis, A.; Dévéhat, M.L.; Ramos, O.H.P.; Gaillard, C.F.; Susan-Resiga, D.; Cohen, É.A.; Seidah, N.G. 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. Viruses2023, 15, 360.
Essalmani, R.; Andréo, U.; Evagelidis, A.; Dévéhat, M.L.; Ramos, O.H.P.; Gaillard, C.F.; Susan-Resiga, D.; Cohen, É.A.; Seidah, N.G. 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. Viruses 2023, 15, 360.
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. This study investigated the implication of the two cholesterol-regulating convertases SKI-1 and PCSK9 in SARS-CoV-2 entry. We used cell-to-cell fusion assays in HeLa cells and pseudoparticle entry into Calu-3 cells. SKI-1 increases cell-to-cell fusion by enhancing the activation of SREBP-2, whereas PCSK9 reduces cell-to-cell fusion by promoting the cellular degradation of ACE2. Metalloprotease activation is sensitive to enhanced cholesterol levels resulting from SKI-1-activated SREBP-2 that leads to enhanced S2’ formation. However, high metalloprotease activity results in S2’ shedding into a new C-terminal fragment (S2”), leading to reduced cell-to-cell fusion. Indeed, S-mutants that increase S2’’ formation, abolish S2’ and cell-to-cell fusion, as well as pseudoparticles 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 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.
Biology and Life Sciences, Biochemistry and Molecular Biology
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