RT Journal Article
SR Electronic
T1 Angiotensin converting enzyme 2 is a novel target of the γ-secretase complex
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.09.01.277954
DO 10.1101/2020.09.01.277954
A1 Bartolomé, Alberto
A1 Liang, Jiani
A1 Wang, Pengfei
A1 Ho, David D.
A1 Pajvani, Utpal B.
YR 2020
UL http://biorxiv.org/content/early/2020/09/03/2020.09.01.277954.abstract
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.