Control of SARS-CoV-2 infection by MT1-MMP-mediated shedding of ACE2

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.

Circulating ACE2 level and zinc/albumin ratio as potential biomarkers for a precision medicine approach to COVID-19

“…Among other effects downstream of ACE2 pathway, IL-10, an immuno-suppressive cytokine that may drive COVID-19-associated lymphopaenia and eosinopaenia, is early and strongly upregulated during severe SARS-CoV-2 infection ( Montanari et al, 2021 ; Zamai, 2020 , 2021 ), suggesting that circulating ACE2 may predispose to SARS-COV-2 infection. Moreover, soluble ACE2 protein has been shown to not only bind to integrins ( Clarke et al, 2012 ) but also act as a “bridge” for SARS-CoV-2 endocytosis and infection (independently of ACE2 membrane-bound protein) via angiotensin type 1 and/or vasopressin receptors ( Guo et al, 2022 ; Yeung et al, 2021 , 2022 ), indicating that circulating ACE2 may play a pathophysiological role promoting SARS-CoV-2 infection independently of its systemic enzymatic activity. In line with these findings, a clinical trial with intravenously APN01 (a recombinant ACE2 dimer) that was designed to block SARS-CoV-2 cellular entry, was stopped early because of higher both mortality rates and viral loads than controls ( ClinicalTrials.gov, 2021 ), confirming that systemic ACE2 dimer administration can (directly and/or indirectly) affect SARS-CoV-2 infectivity .…”

Alternative Renin-Angiotensin System

“…ACE2 is a dimeric type-1 transmembrane protein consisting of a carboxypeptidase and a collectrin-like domain, which can be cleaved by sheddases such as TMPRSS2 (Transmembrane protease, serine 2), MT1-MMP (Matrix metalloproteinase-14), and ADAM17 (A disintegrin and metalloprotease 17). [99][100][101][102] The SP (signal peptide) is released during synthesis and the mature protein starts with residue 18, a glutamine, which is cyclized forming pyroglutamate. 103 Transmembrane domain (TM), Dimerization domain (DD), active site (AS), sheddase cleavage sites (CS), binding sites for the spike proteins of coronaviruses (V).…”

“…112 In its juxtamembrane region, there are cutting sites for sheddases, such as ADAM17 (A disintegrin and metalloprotease 17), MT1-MMP (Matrix metalloproteinase-14), and TMPRSS2 (Transmembrane protease, serine 2), which release the catalytically active ectodomain, called soluble ACE2 (sACE2). 100,101 The function of sACE2 is still obscure and in particular in COVID-19 it is very controversial, with some groups postulating it to be the main mediator of virus uptake by binding to AT 1 R 101 and others assigning this role solely to the membrane-bound form. 113 Nevertheless, the blood levels of sACE2 became a biomarker for severe COVID-19 114 and other cardiovascular and inflammatory diseases 115 probably because its shedding is mediated by inflammation.…”

“…Figure 4. Structure of human ACE2 (angiotensin-converting enzyme 2).ACE2 is a dimeric type-1 transmembrane protein consisting of a carboxypeptidase and a collectrin-like domain, which can be cleaved by sheddases such as TMPRSS2 (Transmembrane protease, serine 2), MT1-MMP (Matrix metalloproteinase-14), and ADAM17 (A disintegrin and metalloprotease 17) [99][100][101][102]. The SP (signal peptide) is released during synthesis and the mature protein starts with residue 18, a glutamine, which is cyclized forming pyroglutamate 103.…”

Tipping the Balance of Ubiquitination toward a Therapy for COVID-19

“…Clinical trials testing this approach are ongoing ( www.clinicaltrials.gov ID NCT04335136); however, there remains concern that protein instability and insufficient viral–ligand interactions will limit the efficacy of hrsACE2. Another approach to preventing cellular infection with SARS-CoV-2 is to reduce cell-surface ACE2 density by increasing ACE2 shedding ( 4 ) or by augmenting ACE2 cellular internalization ( 5 ). One advantage of therapies based on modifying host cells compared with direct antiviral approaches is that these treatments might be less susceptible to resistance due to viral mutations.…”