Article ; Online: The collectrin-like part of the SARS-CoV-1 and -2 receptor ACE2 is shed by the metalloproteinases ADAM10 and ADAM17.
2022 Volume 36, Issue 3, Page(s) e22234
Abstract: The transmembrane protease angiotensin converting enzyme 2 (ACE2) is a protective regulator within the renin angiotensin system and additionally represents the cellular receptor for SARS-CoV. The release of soluble ACE2 (sACE2) from the cell surface is ... ...
| Abstract | The transmembrane protease angiotensin converting enzyme 2 (ACE2) is a protective regulator within the renin angiotensin system and additionally represents the cellular receptor for SARS-CoV. The release of soluble ACE2 (sACE2) from the cell surface is hence believed to be a crucial part of its (patho)physiological functions, as both, ACE2 protease activity and SARS-CoV binding ability, are transferred from the cell membrane to body fluids. Yet, the molecular sources of sACE2 are still not completely investigated. In this study, we show different sources and prerequisites for the release of sACE2 from the cell membrane. By using inhibitors as well as CRISPR/Cas9-derived cells, we demonstrated that, in addition to the metalloprotease ADAM17, also ADAM10 is an important novel shedding protease of ACE2. Moreover, we observed that ACE2 can also be released in extracellular vesicles. The degree of either ADAM10- or ADAM17-mediated ACE2 shedding is dependent on stimulatory conditions and on the expression level of the pro-inflammatory ADAM17 regulator iRhom2. Finally, by using structural analysis and in vitro verification, we determined for the first time that the susceptibility to ADAM10- and ADAM17-mediated shedding is mediated by the collectrin-like part of ACE2. Overall, our findings give novel insights into sACE2 release by several independent molecular mechanisms. |
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| MeSH term(s) | ADAM10 Protein/genetics ; ADAM10 Protein/metabolism ; ADAM17 Protein/genetics ; ADAM17 Protein/metabolism ; Amyloid Precursor Protein Secretases/genetics ; Amyloid Precursor Protein Secretases/metabolism ; Angiotensin-Converting Enzyme 2/genetics ; Angiotensin-Converting Enzyme 2/metabolism ; Clustered Regularly Interspaced Short Palindromic Repeats ; Extracellular Vesicles/genetics ; Extracellular Vesicles/metabolism ; HEK293 Cells ; Humans ; Intracellular Signaling Peptides and Proteins/genetics ; Intracellular Signaling Peptides and Proteins/metabolism ; Membrane Glycoproteins/genetics ; Membrane Glycoproteins/metabolism ; Membrane Proteins/genetics ; Membrane Proteins/metabolism ; SARS Virus/genetics ; SARS Virus/metabolism ; SARS-CoV-2 | ||||||||||
| Chemical Substances | CLTRN protein, human ; Intracellular Signaling Peptides and Proteins ; Membrane Glycoproteins ; Membrane Proteins ; RHBDF2 protein, human ; Amyloid Precursor Protein Secretases (EC 3.4.-) ; ACE2 protein, human (EC 3.4.17.23) ; Angiotensin-Converting Enzyme 2 (EC 3.4.17.23) ; ADAM10 Protein (EC 3.4.24.81) ; ADAM10 protein, human (EC 3.4.24.81) ; ADAM17 Protein (EC 3.4.24.86) ; ADAM17 protein, human (EC 3.4.24.86) | ||||||||||
| Language | English | ||||||||||
| Publishing date | 2022-02-23 | ||||||||||
| Publishing country | United States | ||||||||||
| Document type | Journal Article ; Research Support, Non-U.S. Gov't | ||||||||||
| ZDB-ID | 639186-2 | ||||||||||
| ISSN | 1530-6860 ; 0892-6638 | ||||||||||
| ISSN (online) | 1530-6860 | ||||||||||
| ISSN | 0892-6638 | ||||||||||
| DOI | 10.1096/fj.202101521R | ||||||||||
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| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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