Control of SARS-CoV-2 infection by MT1-MMP-mediated shedding of ACE2.
Nat Commun
; 13(1): 7907, 2022 12 23.
Article
em En
| MEDLINE
| ID: mdl-36564389
ABSTRACT
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global pandemic. Angiotensin-converting enzyme 2 (ACE2) is an entry receptor for SARS-CoV-2. The full-length membrane form of ACE2 (memACE2) undergoes ectodomain shedding to generate a shed soluble form (solACE2) that mediates SARS-CoV-2 entry via receptor-mediated endocytosis. Currently, it is not known how the physiological regulation of ACE2 shedding contributes to the etiology of COVID-19 in vivo. The present study identifies Membrane-type 1 Matrix Metalloproteinase (MT1-MMP) as a critical host protease for solACE2-mediated SARS-CoV-2 infection. SARS-CoV-2 infection leads to increased activation of MT1-MMP that is colocalized with ACE2 in human lung epithelium. Mechanistically, MT1-MMP directly cleaves memACE2 at M706-S to release solACE218-706 that binds to the SARS-CoV-2 spike proteins (S), thus facilitating cell entry of SARS-CoV-2. Human solACE218-706 enables SARS-CoV-2 infection in both non-permissive cells and naturally insusceptible C57BL/6 mice. Inhibition of MT1-MMP activities suppresses solACE2-directed entry of SARS-CoV-2 in human organoids and aged mice. Both solACE2 and circulating MT1-MMP are positively correlated in plasma of aged mice and humans. Our findings provide in vivo evidence demonstrating the contribution of ACE2 shedding to the etiology of COVID-19.
Texto completo:
1
Coleções:
01-internacional
Contexto em Saúde:
1_ASSA2030
/
4_TD
Base de dados:
MEDLINE
Assunto principal:
Metaloproteinase 14 da Matriz
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Interações Hospedeiro-Patógeno
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Enzima de Conversão de Angiotensina 2
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SARS-CoV-2
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COVID-19
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Humans
Idioma:
En
Revista:
Nat Commun
Ano de publicação:
2022
Tipo de documento:
Article