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

On December 23, 2022, Hoi Leong Xavier Wong, School of Chinese Medicine, Hong Kong Baptist University, China, and his team published a paper titled “Control of SARS-CoV-2 infection by MT1-MMP-mediated shedding of ACE2” in Nature Communications. Their findings provide in vivo evidence demonstrating the contribution of ACE2 shedding to the etiology of COVID-19.

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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 Membranetype 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.

Fig.1 The shedding of ACE2 by MT1-MMP

Fig.2 MT1-MMP-mediated ACE2 shedding mediates the SARS-CoV-2 cell entry in vitro and in vivo

Fig.3 Pharmacological inhibition of MT1-MMP confers protection against SARS-CoV-2 infection in aged mice