Tumor Necrosis Factor-α Convertase (ADAM17) Mediates Regulated Ectodomain Shedding of the Severe-acute Respiratory Syndrome-Coronavirus (SARS-CoV) Receptor, Angiotensin-converting Enzyme-2 (ACE2)

Abstract

Angiotensin-converting enzyme-2 (ACE2) is a critical regulator of heart function and a cellular receptor for the causative agent of severe-acute respiratory syndrome (SARS), SARS-CoV (coronavirus). ACE2 is a type I transmembrane protein, with an extracellular N-terminal domain containing the active site and a short intracellular C-terminal tail. A soluble form of ACE2, lacking its cytosolic and transmembrane domains, has been shown to block binding of the SARS-CoV spike protein to its receptor. In this study, we examined the ability of ACE2 to undergo proteolytic shedding and investigated the mechanisms responsible for this shedding event. We demonstrated that ACE2, heterologously expressed in HEK293 cells and endogenously expressed in Huh7 cells, undergoes metalloproteinase-mediated, phorbol ester-inducible ectodomain shedding. By using inhibitors with differing potency toward different members of the ADAM (a disintegrin and metalloproteinase) family of proteases, we identified ADAM17 as a candidate mediator of stimulated ACE2 shedding. Furthermore, ablation of ADAM17 expression using specific small interfering RNA duplexes reduced regulated ACE2 shedding, whereas overexpression of ADAM17 significantly increased shedding. Taken together, these data provided direct evidence for the involvement of ADAM17 in the regulated ectodomain shedding of ACE2. The identification of ADAM17 as the protease responsible for ACE2 shedding may provide new insight into the physiological roles of ACE2.

Cited by papers we hold 19

• ADAM10 and ADAM17 promote SARS‐CoV‐2 cell entry and spike protein‐mediated lung cell fusion · 2022
  No notice
• ACE2-like carboxypeptidase B38-CAP protects from SARS-CoV-2-induced lung injury · 2021
  Not checked
• The role of cysteine peptidases in coronavirus cell entry and replication: The therapeutic potential of cathepsin inhibitors. · 2020
  Not checked
• Heterogeneous expression of the SARS-Coronavirus-2 receptor ACE2 in the human respiratory tract · 2020
  No notice
• Angiotensin‐converting enzyme 2 ( ACE2 ), SARS‐CoV ‐2 and the pathophysiology of coronavirus disease 2019 ( COVID ‐19) · 2020
  No notice
• Endothelium Infection and Dysregulation by SARS-CoV-2: Evidence and Caveats in COVID-19 · 2020
  No notice
• ACE2: The key Molecule for Understanding the Pathophysiology of Severe and Critical Conditions of COVID-19: Demon or Angel? · 2020
  No notice
• ACE2/ADAM17/TMPRSS2 Interplay May Be the Main Risk Factor for COVID-19 · 2020
  No notice
• The Immune Response and Immunopathology of COVID-19 · 2020
  No notice
• Body Localization of ACE-2: On the Trail of the Keyhole of SARS-CoV-2 · 2020
  No notice
• Inflammation Triggered by SARS-CoV-2 and ACE2 Augment Drives Multiple Organ Failure of Severe COVID-19: Molecular Mechanisms and Implications · 2020
  No notice
• ACE2, Much More Than Just a Receptor for SARS-COV-2 · 2020
  No notice
• Elevated plasma angiotensin converting enzyme 2 activity is an independent predictor of major adverse cardiac events in patients with obstructive coronary artery disease · 2018
  No notice
• Circulating levels of tumor necrosis factor-alpha receptor 2 are increased in heart failure with preserved ejection fraction relative to heart failure with reduced ejection fraction: evidence for a divergence in pathophysiology. · 2014
  Not checked
• Update on the Angiotensin Converting Enzyme 2-Angiotensin (1–7)-Mas Receptor Axis: Fetal Programing, Sex Differences, and Intracellular Pathways · 2014
  No notice
• From gene to protein—experimental and clinical studies of ACE2 in blood pressure control and arterial hypertension · 2014
  No notice
• Rosiglitazone treatment of type 2 diabetic db/db mice attenuates urinary albumin and angiotensin converting enzyme 2 excretion. · 2013
  Not checked
• Inhibition of SARS Pseudovirus Cell Entry by Lactoferrin Binding to Heparan Sulfate Proteoglycans · 2011
  No notice
• Angiotensin‐Converting Enzyme 2: The First Decade · 2011
  No notice

Reads

A person counts once a day per paper. We keep no cookie and no address: a reader is a hash that changes every day. Any month under five reads shows no number.