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

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 γ-secretase (γS) targets, we hypothesized that ACE2 may be affected by γS proteolytic activity. We found that after ectodomain shedding, ACE2 is targeted for intramembrane proteolysis by γS, releasing a soluble ACE2 C-terminal fragment. Consistently, chemical or genetic inhibition of γS results in the accumulation of a membrane-bound fragment of ectodomain-deficient ACE2. Although chemical inhibition of γS does not alter SARS-CoV-2 cell entry, these data point to a novel pathway for cellular ACE2 trafficking.

SUBMITTER: Bartolome A

PROVIDER: S-EPMC8105332 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

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

Bartolomé Alberto A Liang Jiani J Wang Pengfei P Ho David D DD Pajvani Utpal B UB

Scientific reports 20210507 1

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 γ-secretase (γS) targets, we hypothesized that ACE2 may be affected by γS proteolytic activity. We found that after ectodomain shedding, ACE2 is targeted for intramembrane proteolysis by γS, releasing a soluble ACE2 C-terminal fragment. Consistently, chemical or ge ...[more]

PMID: 33963249

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