- cleavage of ACE2 requires Arg and Lys residues within ACE2 amino acids 652-659
- cleavage of ACE2 by ADAM17 does not promote spike protein entry, unlike TMPRSS2
- competes with TMPRSS2 for ACE2 processing

State University of New York at Stony Brook

While the mechanism remains unclear, it has been hypothesized that this type I sheddase transmembrane protein is involved in the pathogenesis of COVID-19.  Evidence that suggests that ADAM17 may be involved include:

- its known role in SARS-CoV viral uptake into host cells
- activating TNF‐α through cleave in cases of lung inflammation
- an association between high ADAM17 tissue expression and TNF‐α in an animal model of COPD, a known risk factor of COVID-19
- elevated ADAM17 gene expression in type II diabetic patients with diabetic low‐density lipoprotein (LDL)
- suggested contribution of ADAM17 to inflammation by stimulating IL-8 release
- proposed role in lung fibrosis and COPD through its ability to cleave IL-6R

ADAM17 in the Pathogenesis of COVID-19

Heurich, A., Hofmann-Winkler, H., Gierer, S., Liepold, T., Jahn, O., & Pöhlmann, S. (2014). TMPRSS2 and ADAM17 cleave ACE2 differentially and only proteolysis by TMPRSS2 augments entry driven by the severe acute respiratory syndrome coronavirus spike protein. Journal of virology, 88(2), 1293-1307.
doi: 10.1128/JVI.02202-13

TMPRSS2 and ADAM17 Cleave ACE2 Differentially and Only Proteolysis by TMPRSS2 Augments Entry Driven by the Severe Acute Respiratory Syndrome Coronavirus Spike Protein

ADAM17 has been demonstrated to upregulate ACE2 expression in cells via a process known as shedding, where it cleaves the extracellular portion of the receptor off of the cell.  Increased ACE2 receptors increases the number of SARS-CoV-2 viral receptors on the cellular surface, and this may exacerbate the infection or COVID-19 symptoms.  

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