Faculty, Staff and Student Publications

Language

English

Publication Date

12-23-2022

Journal

Nature Communications

DOI

10.1038/s41467-022-35590-x

PMID

36564389

PMCID

PMC9780620

PubMedCentral® Posted Date

12-23-2022

PubMedCentral® Full Text Version

Post-print

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 solACE2

Keywords

Animals, Humans, Mice, Angiotensin-Converting Enzyme 2, COVID-19, Matrix Metalloproteinase 14, Mice, Inbred C57BL, Peptidyl-Dipeptidase A, SARS-CoV-2, Spike Glycoprotein, Coronavirus, Host-Pathogen Interactions

Published Open-Access

yes

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