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bioRxiv · 10.1101/2020.09.01.277954

Angiotensin converting enzyme 2 is a novel target of the γ-secretase complex

Bartolome, A.·Liang, J.·Wang, P.·Ho, D. D.·Pajvani, U. B.
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Abstract

Angiotensin converting enzyme 2 (ACE2) is a key regulator of the renin-angiotensin system, but also the functional receptor of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Based on structural similarity with other {gamma}-secretase ({gamma}S) targets, we hypothesized that ACE2 may be affected by {gamma}S proteolytic activity. We found that after ectodomain shedding, ACE2 is targeted for intramembrane proteolysis by {gamma}S, releasing a soluble ACE2 C-terminal fragment. Consistently, chemical or genetic inhibition of {gamma}S results in the accumulation of a membrane-bound fragment of ectodomain-deficient ACE2. Although chemical inhibition of {gamma}S does not alter SARS-CoV-2 cell entry, these data point to a novel pathway for cellular ACE2 trafficking.

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Bartolome, A., Liang, J., Wang, P., Ho, D. D., Pajvani, U. B.. 2020-09-03. Angiotensin converting enzyme 2 is a novel target of the γ-secretase complex. https://doi.org/10.1101/2020.09.01.277954

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