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)

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