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

View ORCID ProfileAlberto Bartolomé, Jiani Liang, Pengfei Wang, David D. Ho, View ORCID ProfileUtpal B. Pajvani
doi: https://doi.org/10.1101/2020.09.01.277954
Alberto Bartolomé
1Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA
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Jiani Liang
1Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA
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Pengfei Wang
2Aaron Diamond AIDS Research Center, Columbia University Irving Medical Center, New York, NY, USA
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David D. Ho
2Aaron Diamond AIDS Research Center, Columbia University Irving Medical Center, New York, NY, USA
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Utpal B. Pajvani
1Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA
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  • ORCID record for Utpal B. Pajvani
  • For correspondence: up2104@cumc.columbia.edu
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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 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.

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Posted September 03, 2020.
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Angiotensin converting enzyme 2 is a novel target of the γ-secretase complex
Alberto Bartolomé, Jiani Liang, Pengfei Wang, David D. Ho, Utpal B. Pajvani
bioRxiv 2020.09.01.277954; doi: https://doi.org/10.1101/2020.09.01.277954
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Angiotensin converting enzyme 2 is a novel target of the γ-secretase complex
Alberto Bartolomé, Jiani Liang, Pengfei Wang, David D. Ho, Utpal B. Pajvani
bioRxiv 2020.09.01.277954; doi: https://doi.org/10.1101/2020.09.01.277954

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