PT  - JOURNAL ARTICLE
AU  - Bartolomé, Alberto
AU  - Liang, Jiani
AU  - Wang, Pengfei
AU  - Ho, David D.
AU  - Pajvani, Utpal B.
TI  - Angiotensin converting enzyme 2 is a novel target of the γ-secretase complex
AID  - 10.1101/2020.09.01.277954
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.09.01.277954
4099  - http://biorxiv.org/content/early/2020/09/03/2020.09.01.277954.short
4100  - http://biorxiv.org/content/early/2020/09/03/2020.09.01.277954.full
AB  - 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.