Key result
TMPRSS2 knockout increases tissue ACE2 levels by altering its processing and cellular localization.
Why the study?
This study aimed to elucidate the relationship between ACE2 and TMPRSS2 and the mechanism of ACE2 processing under normal cellular conditions.
Does TMPRSS2 regulate ACE2 trafficking and shedding in cellular and rat models?
Does TMPRSS2 regulate ACE2 trafficking and shedding in cellular and rat models?
This study demonstrates that TMPRSS2 plays a critical role in regulating ACE2 shedding and trafficking in vivo, which has implications for understanding SARS-CoV-2 pathology.
Highlights TMPRSS2 as potential antiviral target; leaves open whether inhibition improves COVID-19 outcomes.
Angiotensin-converting enzyme 2 (ACE2) functions as the receptor for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The virus utilizes the cellular endocytic machinery for entry by binding to defined residues on ACE2 with its spike protein (S protein), whose activation requires a priming process by another transmembrane protease, the transmembrane protease serine 2 (TMPRSS2). In addition, ACE2 itself is cleaved by TMPRSS2, which has been shown to be critical for viral pathology. This study aimed to elucidate the relationship between ACE2 and TMPRSS2 and the mechanism of ACE2 processing under normal cellular conditions. It is shown that interaction of ACE2 with TMPRSS2 results in altered processing, modification and cellular localization. Glycosylation of ACE2 has a major impact on TMPRSS2 interaction, trafficking and shedding of the enzyme. Studies in newly generated TMPRSS2-knockout rats reveal increased ACE2 levels in tissues supporting an important role of TMPRSS2 in ACE2 shedding also in vivo.
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Qiu et al. (2026) studied this question. TMPRSS2 knockout was evaluated on ACE2 processing, modification, cellular localization, and shedding. TMPRSS2 interacts with ACE2 to alter its processing, modification, and cellular localization, with TMPRSS2-knockout rats demonstrating increased ACE2 levels in tissues.
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