TMPRSS2 and ADAM17 Cleave ACE2 Differentially and Only Proteolysis by TMPRSS2 Augments Entry Driven by the Severe Acute Respiratory Syndrome Coronavirus Spike Protein
By Adeline Heurich, Heike Hofmann-Winkler, Stefanie Gierer, T. Liepold, O. Jahn, S. Pöhlmann. Journal of Virology, 2013
824 citations recorded by the source corpus.
ABSTRACT The type II transmembrane serine proteases TMPRSS2 and HAT can cleave and activate the spike protein (S) of the severe acute respiratory syndrome coronavirus (SARS-CoV) for membrane fusion. In addition, these proteases cleave the viral receptor, the carboxypeptidase angiotensin-converting enzyme 2 (ACE2), and it was proposed that ACE2 cleavage augments viral infectivity. However, no mechanistic insights into this process were obtained and the relevance of ACE2 cleavage for SARS-CoV S protein (SARS-S) activation has not been determined. Here, we show that arginine and lysine residues within ACE2 amino acids 697 to 716 are essential for cleavage by TMPRSS2 and HAT and that ACE2 processing is required for augmentation of SARS-S-driven entry by these proteases. In contrast, ACE2 cleavage was dispensable for activation of the viral S protein. Expression of TMPRSS2 increased cellular uptake of soluble SARS-S, suggesting that protease-dependent augmentation of viral entry might be due to increased uptake of virions into target cells. Finally, TMPRSS2 was found to compete with the metalloprotease ADAM17 for ACE2 processing, but only cleavage by TMPRSS2 resulted in augmented SARS-S-driven entry. Collectively, our results in conjunction with those of previous studies indicate that TMPRSS2 and potentially related proteases promote SARS-CoV entry by two separate mechanisms: ACE2 cleavage, which might promote viral uptake, and SARS-S cleavage, which activates the S protein for membrane fusion. These observations have interesting implications for the development of novel therapeutics. In addition, they should spur efforts to determine whether receptor cleavage promotes entry of other coronaviruses, which use peptidases as entry receptors.
Subfields: Animal Science and Zoology, Infectious Diseases
View Paper: https://www.semanticscholar.org/paper/988a5abe7132f41106e4da1cc1998b6a8337b23c
How researchers see this paper
The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.
- Mazhar Salim Al Zoubi
- Amjad D. Al-Nasser
- Firas A. Rabi
- Ghena A Kasasbeh
- Dunia M Salameh
- I. Astuti
Citations in the corpus
- SARS-CoV-2 and Coronavirus Disease 2019: What We Know So Far (2020, result): “It has been demonstrated that when the SARS spike protein binds to the ACE-2 receptor ( Figure 3A ), the complex is proteolytically processed by type 2 transmembrane protease TMPRSS2 leading to cleavage of ACE-2 and activation of the spike protein ( Figure 3B ) [21, 22] , similar to the mechanism em”
- SARS-CoV-2 variants B.1.351 and P.1 escape from neutralizing antibodies (2021, neutral): “, 2013), TMPRSS2 (Heurich et al., 2014), Gal4-TurboGFP-Luc and Vp16-Gal4 (Hörnich et al.”