tetano
Editor, Senior Moderator
iScience
. 2022 Oct 10;105316.
doi: 10.1016/j.isci.2022.105316. Online ahead of print.
Identification and differential usage of a host metalloproteinase entry pathway by SARS-CoV-2 Delta and Omicron
Mehdi Benlarbi[SUP] 1 2 3 [/SUP], Geneviève Laroche[SUP] 1 2 3 [/SUP], Corby Fink[SUP] 4 5 [/SUP], Kathy Fu[SUP] 1 2 3 [/SUP], Rory P Mulloy[SUP] 1 2 3 [/SUP], Alexandra Phan[SUP] 1 2 3 [/SUP], Ardeshir Ariana[SUP] 1 2 3 [/SUP], Corina M Stewart[SUP] 1 2 3 [/SUP], Jérémie Prévost[SUP] 6 7 [/SUP], Guillaume Beaudoin-Bussières[SUP] 6 7 [/SUP], Redaet Daniel[SUP] 1 2 3 [/SUP], Yuxia Bo[SUP] 1 2 3 [/SUP], Omar El Ferri[SUP] 1 2 3 [/SUP], Julien Yockell-Lelièvre[SUP] 1 2 8 9 [/SUP], William L Stanford[SUP] 1 2 8 9 [/SUP], Patrick M Giguère[SUP] 1 [/SUP], Samira Mubareka[SUP] 10 11 [/SUP], Andrés Finzi[SUP] 6 7 [/SUP], Gregory A Dekaban[SUP] 4 5 [/SUP], Jimmy D Dikeakos[SUP] 4 5 [/SUP], Marceline Côté[SUP] 1 2 3 [/SUP]
Affiliations
Abstract
The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) spike glycoprotein (S) binds to angiotensin-converting enzyme 2 (ACE2) to mediate membrane fusion via two distinct pathways: 1) a surface, serine protease-dependent or 2) an endosomal, cysteine protease-dependent pathway. In this study, we found that SARS-CoV-2 S has a wider protease usage and can also be activated by TMPRSS13 and matrix metalloproteinases (MMPs). We found that MMP-2 and MMP-9 played roles in SARS-CoV-2 S cell-cell fusion and TMPRSS2- and cathepsin-independent viral entry in cells expressing high MMP levels. MMP-dependent viral entry required cleavage at the S1/S2 junction in viral producer cells, and differential processing of variants of concern S dictated its usage; the efficiently processed Delta S preferred metalloproteinase-dependent entry when available, and less processed Omicron S was unable to us metalloproteinases for entry. As MMP-2/9 are released during inflammation, they may play roles in S-mediated cytopathic effects, tropism, and disease outcome.
Keywords: SARS-CoV-2; Spike glycoprotein; membrane fusion; metalloproteinases; variants of concern; viral entry.
. 2022 Oct 10;105316.
doi: 10.1016/j.isci.2022.105316. Online ahead of print.
Identification and differential usage of a host metalloproteinase entry pathway by SARS-CoV-2 Delta and Omicron
Mehdi Benlarbi[SUP] 1 2 3 [/SUP], Geneviève Laroche[SUP] 1 2 3 [/SUP], Corby Fink[SUP] 4 5 [/SUP], Kathy Fu[SUP] 1 2 3 [/SUP], Rory P Mulloy[SUP] 1 2 3 [/SUP], Alexandra Phan[SUP] 1 2 3 [/SUP], Ardeshir Ariana[SUP] 1 2 3 [/SUP], Corina M Stewart[SUP] 1 2 3 [/SUP], Jérémie Prévost[SUP] 6 7 [/SUP], Guillaume Beaudoin-Bussières[SUP] 6 7 [/SUP], Redaet Daniel[SUP] 1 2 3 [/SUP], Yuxia Bo[SUP] 1 2 3 [/SUP], Omar El Ferri[SUP] 1 2 3 [/SUP], Julien Yockell-Lelièvre[SUP] 1 2 8 9 [/SUP], William L Stanford[SUP] 1 2 8 9 [/SUP], Patrick M Giguère[SUP] 1 [/SUP], Samira Mubareka[SUP] 10 11 [/SUP], Andrés Finzi[SUP] 6 7 [/SUP], Gregory A Dekaban[SUP] 4 5 [/SUP], Jimmy D Dikeakos[SUP] 4 5 [/SUP], Marceline Côté[SUP] 1 2 3 [/SUP]
Affiliations
- PMID: 36254158
- PMCID: PMC9549715
- DOI: 10.1016/j.isci.2022.105316
Abstract
The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) spike glycoprotein (S) binds to angiotensin-converting enzyme 2 (ACE2) to mediate membrane fusion via two distinct pathways: 1) a surface, serine protease-dependent or 2) an endosomal, cysteine protease-dependent pathway. In this study, we found that SARS-CoV-2 S has a wider protease usage and can also be activated by TMPRSS13 and matrix metalloproteinases (MMPs). We found that MMP-2 and MMP-9 played roles in SARS-CoV-2 S cell-cell fusion and TMPRSS2- and cathepsin-independent viral entry in cells expressing high MMP levels. MMP-dependent viral entry required cleavage at the S1/S2 junction in viral producer cells, and differential processing of variants of concern S dictated its usage; the efficiently processed Delta S preferred metalloproteinase-dependent entry when available, and less processed Omicron S was unable to us metalloproteinases for entry. As MMP-2/9 are released during inflammation, they may play roles in S-mediated cytopathic effects, tropism, and disease outcome.
Keywords: SARS-CoV-2; Spike glycoprotein; membrane fusion; metalloproteinases; variants of concern; viral entry.