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

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.