Tumor necrosis factor-alpha convertase (ADAM17) mediates regulated ectodomain shedding of the severe-acute respiratory syndrome-coronavirus (SARS-CoV) receptor, angiotensin-converting enzyme-2 (ACE2).
Identifieur interne : 004576 ( Main/Exploration ); précédent : 004575; suivant : 004577Tumor necrosis factor-alpha convertase (ADAM17) mediates regulated ectodomain shedding of the severe-acute respiratory syndrome-coronavirus (SARS-CoV) receptor, angiotensin-converting enzyme-2 (ACE2).
Auteurs : Daniel W. Lambert [Royaume-Uni] ; Mike Yarski ; Fiona J. Warner ; Paul Thornhill ; Edward T. Parkin ; A Ian Smith ; Nigel M. Hooper ; Anthony J. TurnerSource :
- The Journal of biological chemistry [ 0021-9258 ] ; 2005.
Descripteurs français
- KwdFr :
- ADN complémentaire (métabolisme), ARN (), ARN double brin (), Amyloid precursor protein secretases, Aspartic acid endopeptidases (métabolisme), Carboxypeptidases (métabolisme), Cytoplasme (métabolisme), Désintégrines (métabolisme), Endopeptidases, Esters de phorbol, Facteurs temps, Humains, Immunotransfert, Isoformes de protéines (), Liaison aux protéines, Lignée cellulaire, Metalloendopeptidases (), Metalloendopeptidases (métabolisme), Metalloendopeptidases (physiologie), Peptide hydrolases (métabolisme), Peptides (), Peptidyl-Dipeptidase A, Petit ARN interférent (métabolisme), Plasmides (métabolisme), Protéine ADAM17, Protéines ADAM, Protéines membranaires (métabolisme), Sites de fixation, Structure tertiaire des protéines, Transfection, Virus du SRAS (métabolisme), Électrophorèse sur gel de polyacrylamide.
- MESH :
- métabolisme : ADN complémentaire, Aspartic acid endopeptidases, Carboxypeptidases, Cytoplasme, Désintégrines, Metalloendopeptidases, Peptide hydrolases, Petit ARN interférent, Plasmides, Protéines membranaires, Virus du SRAS.
- physiologie : Metalloendopeptidases.
- ARN, ARN double brin, Amyloid precursor protein secretases, Endopeptidases, Esters de phorbol, Facteurs temps, Humains, Immunotransfert, Isoformes de protéines, Liaison aux protéines, Lignée cellulaire, Metalloendopeptidases, Peptides, Peptidyl-Dipeptidase A, Protéine ADAM17, Protéines ADAM, Sites de fixation, Structure tertiaire des protéines, Transfection, Électrophorèse sur gel de polyacrylamide.
English descriptors
- KwdEn :
- ADAM Proteins, ADAM17 Protein, Amyloid Precursor Protein Secretases, Aspartic Acid Endopeptidases (metabolism), Binding Sites, Carboxypeptidases (metabolism), Cell Line, Cytoplasm (metabolism), DNA, Complementary (metabolism), Disintegrins (metabolism), Electrophoresis, Polyacrylamide Gel, Endopeptidases, Humans, Immunoblotting, Membrane Proteins (metabolism), Metalloendopeptidases (chemistry), Metalloendopeptidases (metabolism), Metalloendopeptidases (physiology), Peptide Hydrolases (metabolism), Peptides (chemistry), Peptidyl-Dipeptidase A, Phorbol Esters, Plasmids (metabolism), Protein Binding, Protein Isoforms (chemistry), Protein Structure, Tertiary, RNA (chemistry), RNA, Double-Stranded (chemistry), RNA, Small Interfering (metabolism), SARS Virus (metabolism), Time Factors, Transfection.
- MESH :
- chemical , chemistry : Metalloendopeptidases, Peptides, Protein Isoforms, RNA, RNA, Double-Stranded.
- chemical , metabolism : Aspartic Acid Endopeptidases, Carboxypeptidases, DNA, Complementary, Disintegrins, Membrane Proteins, Metalloendopeptidases, Peptide Hydrolases, RNA, Small Interfering.
- chemical , physiology : Metalloendopeptidases.
- chemical : ADAM Proteins, ADAM17 Protein, Amyloid Precursor Protein Secretases, Endopeptidases, Peptidyl-Dipeptidase A, Phorbol Esters.
- metabolism : Cytoplasm, Plasmids, SARS Virus.
- Binding Sites, Cell Line, Electrophoresis, Polyacrylamide Gel, Humans, Immunoblotting, Protein Binding, Protein Structure, Tertiary, Time Factors, Transfection.
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.
DOI: 10.1074/jbc.M505111200
PubMed: 15983030
Affiliations:
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Lambert</name><affiliation wicri:level="4"><nlm:affiliation>Proteolysis Research Group, School of Biochemistry and Microbiology, University of Leeds, Leeds LS2 9JT, United Kingdom. d.w.lambert@leeds.ac.uk</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Proteolysis Research Group, School of Biochemistry and Microbiology, University of Leeds, Leeds LS2 9JT</wicri:regionArea><orgName type="university">Université de Leeds</orgName><placeName><settlement type="city">Leeds</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Yorkshire-et-Humber</region></placeName></affiliation></author><author><name sortKey="Yarski, Mike" sort="Yarski, Mike" uniqKey="Yarski M" first="Mike" last="Yarski">Mike Yarski</name></author><author><name sortKey="Warner, Fiona J" sort="Warner, Fiona J" uniqKey="Warner F" first="Fiona J" last="Warner">Fiona J. 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Lambert</name><affiliation wicri:level="4"><nlm:affiliation>Proteolysis Research Group, School of Biochemistry and Microbiology, University of Leeds, Leeds LS2 9JT, United Kingdom. d.w.lambert@leeds.ac.uk</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Proteolysis Research Group, School of Biochemistry and Microbiology, University of Leeds, Leeds LS2 9JT</wicri:regionArea><orgName type="university">Université de Leeds</orgName><placeName><settlement type="city">Leeds</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Yorkshire-et-Humber</region></placeName></affiliation></author><author><name sortKey="Yarski, Mike" sort="Yarski, Mike" uniqKey="Yarski M" first="Mike" last="Yarski">Mike Yarski</name></author><author><name sortKey="Warner, Fiona J" sort="Warner, Fiona J" uniqKey="Warner F" first="Fiona J" last="Warner">Fiona J. Warner</name></author><author><name sortKey="Thornhill, Paul" sort="Thornhill, Paul" uniqKey="Thornhill P" first="Paul" last="Thornhill">Paul Thornhill</name></author><author><name sortKey="Parkin, Edward T" sort="Parkin, Edward T" uniqKey="Parkin E" first="Edward T" last="Parkin">Edward T. Parkin</name></author><author><name sortKey="Smith, A Ian" sort="Smith, A Ian" uniqKey="Smith A" first="A Ian" last="Smith">A Ian Smith</name></author><author><name sortKey="Hooper, Nigel M" sort="Hooper, Nigel M" uniqKey="Hooper N" first="Nigel M" last="Hooper">Nigel M. Hooper</name></author><author><name sortKey="Turner, Anthony J" sort="Turner, Anthony J" uniqKey="Turner A" first="Anthony J" last="Turner">Anthony J. Turner</name></author></analytic><series><title level="j">The Journal of biological chemistry</title><idno type="ISSN">0021-9258</idno><imprint><date when="2005" type="published">2005</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>ADAM Proteins</term><term>ADAM17 Protein</term><term>Amyloid Precursor Protein Secretases</term><term>Aspartic Acid Endopeptidases (metabolism)</term><term>Binding Sites</term><term>Carboxypeptidases (metabolism)</term><term>Cell Line</term><term>Cytoplasm (metabolism)</term><term>DNA, Complementary (metabolism)</term><term>Disintegrins (metabolism)</term><term>Electrophoresis, Polyacrylamide Gel</term><term>Endopeptidases</term><term>Humans</term><term>Immunoblotting</term><term>Membrane Proteins (metabolism)</term><term>Metalloendopeptidases (chemistry)</term><term>Metalloendopeptidases (metabolism)</term><term>Metalloendopeptidases (physiology)</term><term>Peptide Hydrolases (metabolism)</term><term>Peptides (chemistry)</term><term>Peptidyl-Dipeptidase A</term><term>Phorbol Esters</term><term>Plasmids (metabolism)</term><term>Protein Binding</term><term>Protein Isoforms (chemistry)</term><term>Protein Structure, Tertiary</term><term>RNA (chemistry)</term><term>RNA, Double-Stranded (chemistry)</term><term>RNA, Small Interfering (metabolism)</term><term>SARS Virus (metabolism)</term><term>Time Factors</term><term>Transfection</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>ADN complémentaire (métabolisme)</term><term>ARN ()</term><term>ARN double brin ()</term><term>Amyloid precursor protein secretases</term><term>Aspartic acid endopeptidases (métabolisme)</term><term>Carboxypeptidases (métabolisme)</term><term>Cytoplasme (métabolisme)</term><term>Désintégrines (métabolisme)</term><term>Endopeptidases</term><term>Esters de phorbol</term><term>Facteurs temps</term><term>Humains</term><term>Immunotransfert</term><term>Isoformes de protéines ()</term><term>Liaison aux protéines</term><term>Lignée cellulaire</term><term>Metalloendopeptidases ()</term><term>Metalloendopeptidases (métabolisme)</term><term>Metalloendopeptidases (physiologie)</term><term>Peptide hydrolases (métabolisme)</term><term>Peptides ()</term><term>Peptidyl-Dipeptidase A</term><term>Petit ARN interférent (métabolisme)</term><term>Plasmides (métabolisme)</term><term>Protéine ADAM17</term><term>Protéines ADAM</term><term>Protéines membranaires (métabolisme)</term><term>Sites de fixation</term><term>Structure tertiaire des protéines</term><term>Transfection</term><term>Virus du SRAS (métabolisme)</term><term>Électrophorèse sur gel de polyacrylamide</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Metalloendopeptidases</term><term>Peptides</term><term>Protein Isoforms</term><term>RNA</term><term>RNA, Double-Stranded</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Aspartic Acid Endopeptidases</term><term>Carboxypeptidases</term><term>DNA, Complementary</term><term>Disintegrins</term><term>Membrane Proteins</term><term>Metalloendopeptidases</term><term>Peptide Hydrolases</term><term>RNA, Small Interfering</term></keywords><keywords scheme="MESH" type="chemical" qualifier="physiology" xml:lang="en"><term>Metalloendopeptidases</term></keywords><keywords scheme="MESH" type="chemical" xml:lang="en"><term>ADAM Proteins</term><term>ADAM17 Protein</term><term>Amyloid Precursor Protein Secretases</term><term>Endopeptidases</term><term>Peptidyl-Dipeptidase A</term><term>Phorbol Esters</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Cytoplasm</term><term>Plasmids</term><term>SARS Virus</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>ADN complémentaire</term><term>Aspartic acid endopeptidases</term><term>Carboxypeptidases</term><term>Cytoplasme</term><term>Désintégrines</term><term>Metalloendopeptidases</term><term>Peptide hydrolases</term><term>Petit ARN interférent</term><term>Plasmides</term><term>Protéines membranaires</term><term>Virus du SRAS</term></keywords><keywords scheme="MESH" qualifier="physiologie" xml:lang="fr"><term>Metalloendopeptidases</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Binding Sites</term><term>Cell Line</term><term>Electrophoresis, Polyacrylamide Gel</term><term>Humans</term><term>Immunoblotting</term><term>Protein Binding</term><term>Protein Structure, Tertiary</term><term>Time Factors</term><term>Transfection</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>ARN</term><term>ARN double brin</term><term>Amyloid precursor protein secretases</term><term>Endopeptidases</term><term>Esters de phorbol</term><term>Facteurs temps</term><term>Humains</term><term>Immunotransfert</term><term>Isoformes de protéines</term><term>Liaison aux protéines</term><term>Lignée cellulaire</term><term>Metalloendopeptidases</term><term>Peptides</term><term>Peptidyl-Dipeptidase A</term><term>Protéine ADAM17</term><term>Protéines ADAM</term><term>Sites de fixation</term><term>Structure tertiaire des protéines</term><term>Transfection</term><term>Électrophorèse sur gel de polyacrylamide</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">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.</div></front></TEI><affiliations><list><country><li>Royaume-Uni</li></country><region><li>Angleterre</li><li>Yorkshire-et-Humber</li></region><settlement><li>Leeds</li></settlement><orgName><li>Université de Leeds</li></orgName></list><tree><noCountry><name sortKey="Hooper, Nigel M" sort="Hooper, Nigel M" uniqKey="Hooper N" first="Nigel M" last="Hooper">Nigel M. Hooper</name><name sortKey="Parkin, Edward T" sort="Parkin, Edward T" uniqKey="Parkin E" first="Edward T" last="Parkin">Edward T. Parkin</name><name sortKey="Smith, A Ian" sort="Smith, A Ian" uniqKey="Smith A" first="A Ian" last="Smith">A Ian Smith</name><name sortKey="Thornhill, Paul" sort="Thornhill, Paul" uniqKey="Thornhill P" first="Paul" last="Thornhill">Paul Thornhill</name><name sortKey="Turner, Anthony J" sort="Turner, Anthony J" uniqKey="Turner A" first="Anthony J" last="Turner">Anthony J. Turner</name><name sortKey="Warner, Fiona J" sort="Warner, Fiona J" uniqKey="Warner F" first="Fiona J" last="Warner">Fiona J. Warner</name><name sortKey="Yarski, Mike" sort="Yarski, Mike" uniqKey="Yarski M" first="Mike" last="Yarski">Mike Yarski</name></noCountry><country name="Royaume-Uni"><region name="Angleterre"><name sortKey="Lambert, Daniel W" sort="Lambert, Daniel W" uniqKey="Lambert D" first="Daniel W" last="Lambert">Daniel W. Lambert</name></region></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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