Ectodomain shedding of angiotensin converting enzyme 2 in human airway epithelia
Identifieur interne : 002F91 ( Main/Merge ); précédent : 002F90; suivant : 002F92Ectodomain shedding of angiotensin converting enzyme 2 in human airway epithelia
Auteurs : HONG PENG JIA [États-Unis] ; Dwight C. Look [États-Unis] ; PING TAN [États-Unis] ; LEI SHI [États-Unis] ; Melissa Hickey [États-Unis] ; Lokesh Gakhar [États-Unis] ; Mark C. Chappell [États-Unis] ; Christine Wohlford-Lenane [États-Unis] ; Paul B. Jr Mccray [États-Unis]Source :
- American journal of physiology. Lung cellular and molecular physiology [ 1040-0605 ] ; 2009.
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Abstract
Angiotensin-converting enzyme 2 (ACE2) is a terminal carboxypeptidase and the receptor for the SARS and NL63 coronaviruses (CoV). Loss of ACE2 function is implicated in severe acute respiratory syndrome (SARS) pathogenesis, but little is known about ACE2 biogenesis and activity in the airways. We report that ACE2 is shed from human airway epithelia, a site of SARS-CoV infection. The regulation of ACE2 release was investigated in polarized human airway epithelia. Constitutive generation of soluble ACE2 was inhibited by DPC 333, implicating a disintegrin and metalloprotease 17 (ADAM17). Phorbol ester, ionomycin, endotoxin, and IL-1β and TNFα acutely induced ACE2 release, further supporting that ADAM17 and ADAM10 regulate ACE2 cleavage. Soluble ACE2 was enzymatically active and partially inhibited virus entry into target cells. We determined that the ACE2 cleavage site resides between amino acid 716 and the putative transmembrane domain starting at amino acid 741. To reveal structural determinants underlying ACE2 release, several mutant and chimeric ACE2 proteins were engineered. Neither the juxtamembrane stalk region, transmembrane domain, nor the cytosolic domain was needed for constitutive ACE2 release. Interestingly, a point mutation in the ACE2 ectodomain, L584A, markedly attenuated shedding. The resultant ACE2-L584A mutant trafficked to the cell membrane and facilitated SARS-CoV entry into target cells, suggesting that the ACE2 ectodomain regulates its release and that residue L584 might be part of a putative sheddase "recognition motif." Thus ACE2 must be cell associated to serve as a CoV receptor and soluble ACE2 might play a role in modifying inflammatory processes at the airway mucosal surface.
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Jr Mccray</name><affiliation wicri:level="4"><inist:fA14 i1="01"><s1>Department of Pediatrics, University of Iowa</s1><s2>Iowa City, Iowa</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>3 aut.</sZ><sZ>5 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Iowa</region><settlement type="city">Iowa City</settlement></placeName><orgName type="university">Université de l'Iowa</orgName></affiliation><affiliation wicri:level="4"><inist:fA14 i1="02"><s1>Department of Internal Medicine, University of Iowa</s1><s2>Iowa City, Iowa</s2><s3>USA</s3><sZ>2 aut.</sZ><sZ>4 aut.</sZ><sZ>9 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Iowa</region><settlement type="city">Iowa City</settlement></placeName><orgName type="university">Université de l'Iowa</orgName></affiliation><affiliation wicri:level="4"><inist:fA14 i1="03"><s1>Department of Microbiology, University of Iowa</s1><s2>Iowa City, Iowa</s2><s3>USA</s3><sZ>9 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Iowa</region><settlement type="city">Iowa City</settlement></placeName><orgName type="university">Université de l'Iowa</orgName></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">INIST</idno><idno type="inist">09-0333499</idno><date when="2009">2009</date><idno type="stanalyst">PASCAL 09-0333499 INIST</idno><idno type="RBID">Pascal:09-0333499</idno><idno type="wicri:Area/PascalFrancis/Corpus">000197</idno><idno type="wicri:Area/PascalFrancis/Curation">000791</idno><idno type="wicri:Area/PascalFrancis/Checkpoint">000214</idno><idno type="wicri:explorRef" wicri:stream="PascalFrancis" wicri:step="Checkpoint">000214</idno><idno type="wicri:doubleKey">1040-0605:2009:Hong Peng Jia:ectodomain:shedding:of</idno><idno type="wicri:Area/Main/Merge">002F91</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a">Ectodomain shedding of angiotensin converting enzyme 2 in human airway epithelia</title><author><name sortKey="Hong Peng Jia" sort="Hong Peng Jia" uniqKey="Hong Peng Jia" last="Hong Peng Jia">HONG PENG JIA</name><affiliation wicri:level="4"><inist:fA14 i1="01"><s1>Department of Pediatrics, University of Iowa</s1><s2>Iowa City, Iowa</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>3 aut.</sZ><sZ>5 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Iowa</region><settlement type="city">Iowa City</settlement></placeName><orgName type="university">Université de l'Iowa</orgName></affiliation></author><author><name sortKey="Look, Dwight C" sort="Look, Dwight C" uniqKey="Look D" first="Dwight C." last="Look">Dwight C. Look</name><affiliation wicri:level="4"><inist:fA14 i1="02"><s1>Department of Internal Medicine, University of Iowa</s1><s2>Iowa City, Iowa</s2><s3>USA</s3><sZ>2 aut.</sZ><sZ>4 aut.</sZ><sZ>9 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Iowa</region><settlement type="city">Iowa City</settlement></placeName><orgName type="university">Université de l'Iowa</orgName></affiliation></author><author><name sortKey="Ping Tan" sort="Ping Tan" uniqKey="Ping Tan" last="Ping Tan">PING TAN</name><affiliation wicri:level="4"><inist:fA14 i1="01"><s1>Department of Pediatrics, University of Iowa</s1><s2>Iowa City, Iowa</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>3 aut.</sZ><sZ>5 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Iowa</region><settlement type="city">Iowa City</settlement></placeName><orgName type="university">Université de l'Iowa</orgName></affiliation></author><author><name sortKey="Lei Shi" sort="Lei Shi" uniqKey="Lei Shi" last="Lei Shi">LEI SHI</name><affiliation wicri:level="4"><inist:fA14 i1="02"><s1>Department of Internal Medicine, University of Iowa</s1><s2>Iowa City, Iowa</s2><s3>USA</s3><sZ>2 aut.</sZ><sZ>4 aut.</sZ><sZ>9 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Iowa</region><settlement type="city">Iowa City</settlement></placeName><orgName type="university">Université de l'Iowa</orgName></affiliation></author><author><name sortKey="Hickey, Melissa" sort="Hickey, Melissa" uniqKey="Hickey M" first="Melissa" last="Hickey">Melissa Hickey</name><affiliation wicri:level="4"><inist:fA14 i1="01"><s1>Department of Pediatrics, University of Iowa</s1><s2>Iowa City, Iowa</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>3 aut.</sZ><sZ>5 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Iowa</region><settlement type="city">Iowa City</settlement></placeName><orgName type="university">Université de l'Iowa</orgName></affiliation></author><author><name sortKey="Gakhar, Lokesh" sort="Gakhar, Lokesh" uniqKey="Gakhar L" first="Lokesh" last="Gakhar">Lokesh Gakhar</name><affiliation wicri:level="4"><inist:fA14 i1="04"><s1>Biochemistry, Carver College of Medicine, University of Iowa</s1><s2>Iowa City, Iowa</s2><s3>USA</s3><sZ>6 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Iowa</region><settlement type="city">Iowa City</settlement></placeName><orgName type="university">Université de l'Iowa</orgName></affiliation></author><author><name sortKey="Chappell, Mark C" sort="Chappell, Mark C" uniqKey="Chappell M" first="Mark C." last="Chappell">Mark C. Chappell</name><affiliation wicri:level="2"><inist:fA14 i1="05"><s1>Hypertension Center, Wake Forest University School of Medicine</s1><s2>Winston-Salem, North Carolina</s2><s3>USA</s3><sZ>7 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Caroline du Nord</region></placeName></affiliation></author><author><name sortKey="Wohlford Lenane, Christine" sort="Wohlford Lenane, Christine" uniqKey="Wohlford Lenane C" first="Christine" last="Wohlford-Lenane">Christine Wohlford-Lenane</name><affiliation wicri:level="4"><inist:fA14 i1="01"><s1>Department of Pediatrics, University of Iowa</s1><s2>Iowa City, Iowa</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>3 aut.</sZ><sZ>5 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Iowa</region><settlement type="city">Iowa City</settlement></placeName><orgName type="university">Université de l'Iowa</orgName></affiliation></author><author><name sortKey="Mccray, Paul B Jr" sort="Mccray, Paul B Jr" uniqKey="Mccray P" first="Paul B. Jr" last="Mccray">Paul B. Jr Mccray</name><affiliation wicri:level="4"><inist:fA14 i1="01"><s1>Department of Pediatrics, University of Iowa</s1><s2>Iowa City, Iowa</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>3 aut.</sZ><sZ>5 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Iowa</region><settlement type="city">Iowa City</settlement></placeName><orgName type="university">Université de l'Iowa</orgName></affiliation><affiliation wicri:level="4"><inist:fA14 i1="02"><s1>Department of Internal Medicine, University of Iowa</s1><s2>Iowa City, Iowa</s2><s3>USA</s3><sZ>2 aut.</sZ><sZ>4 aut.</sZ><sZ>9 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Iowa</region><settlement type="city">Iowa City</settlement></placeName><orgName type="university">Université de l'Iowa</orgName></affiliation><affiliation wicri:level="4"><inist:fA14 i1="03"><s1>Department of Microbiology, University of Iowa</s1><s2>Iowa City, Iowa</s2><s3>USA</s3><sZ>9 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Iowa</region><settlement type="city">Iowa City</settlement></placeName><orgName type="university">Université de l'Iowa</orgName></affiliation></author></analytic><series><title level="j" type="main">American journal of physiology. Lung cellular and molecular physiology</title><title level="j" type="abbreviated">Am. j. physiol., Lung cell. mol. physiol.</title><idno type="ISSN">1040-0605</idno><imprint><date when="2009">2009</date></imprint></series></biblStruct></sourceDesc><seriesStmt><title level="j" type="main">American journal of physiology. Lung cellular and molecular physiology</title><title level="j" type="abbreviated">Am. j. physiol., Lung cell. mol. physiol.</title><idno type="ISSN">1040-0605</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Acute</term><term>Human</term><term>Mammalia</term><term>Metalloendopeptidases</term><term>Peptidyl-dipeptidase A</term><term>Respiratory system</term><term>Respiratory tract</term></keywords><keywords scheme="Pascal" xml:lang="fr"><term>Peptidyl-dipeptidase A</term><term>Homme</term><term>Voie respiratoire</term><term>Metalloendopeptidases</term><term>Aigu</term><term>Mammalia</term><term>Appareil respiratoire</term></keywords><keywords scheme="Wicri" type="topic" xml:lang="fr"><term>Homme</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Angiotensin-converting enzyme 2 (ACE2) is a terminal carboxypeptidase and the receptor for the SARS and NL63 coronaviruses (CoV). Loss of ACE2 function is implicated in severe acute respiratory syndrome (SARS) pathogenesis, but little is known about ACE2 biogenesis and activity in the airways. We report that ACE2 is shed from human airway epithelia, a site of SARS-CoV infection. The regulation of ACE2 release was investigated in polarized human airway epithelia. Constitutive generation of soluble ACE2 was inhibited by DPC 333, implicating a disintegrin and metalloprotease 17 (ADAM17). Phorbol ester, ionomycin, endotoxin, and IL-1β and TNFα acutely induced ACE2 release, further supporting that ADAM17 and ADAM10 regulate ACE2 cleavage. Soluble ACE2 was enzymatically active and partially inhibited virus entry into target cells. We determined that the ACE2 cleavage site resides between amino acid 716 and the putative transmembrane domain starting at amino acid 741. To reveal structural determinants underlying ACE2 release, several mutant and chimeric ACE2 proteins were engineered. Neither the juxtamembrane stalk region, transmembrane domain, nor the cytosolic domain was needed for constitutive ACE2 release. Interestingly, a point mutation in the ACE2 ectodomain, L584A, markedly attenuated shedding. The resultant ACE2-L584A mutant trafficked to the cell membrane and facilitated SARS-CoV entry into target cells, suggesting that the ACE2 ectodomain regulates its release and that residue L584 might be part of a putative sheddase "recognition motif." Thus ACE2 must be cell associated to serve as a CoV receptor and soluble ACE2 might play a role in modifying inflammatory processes at the airway mucosal surface.</div></front></TEI><affiliations><list><country><li>États-Unis</li></country><region><li>Caroline du Nord</li><li>Iowa</li></region><settlement><li>Iowa City</li></settlement><orgName><li>Université de l'Iowa</li></orgName></list><tree><country name="États-Unis"><region name="Iowa"><name sortKey="Hong Peng Jia" sort="Hong Peng Jia" uniqKey="Hong Peng Jia" last="Hong Peng Jia">HONG PENG JIA</name></region><name sortKey="Chappell, Mark C" sort="Chappell, Mark C" uniqKey="Chappell M" first="Mark C." last="Chappell">Mark C. Chappell</name><name sortKey="Gakhar, Lokesh" sort="Gakhar, Lokesh" uniqKey="Gakhar L" first="Lokesh" last="Gakhar">Lokesh Gakhar</name><name sortKey="Hickey, Melissa" sort="Hickey, Melissa" uniqKey="Hickey M" first="Melissa" last="Hickey">Melissa Hickey</name><name sortKey="Lei Shi" sort="Lei Shi" uniqKey="Lei Shi" last="Lei Shi">LEI SHI</name><name sortKey="Look, Dwight C" sort="Look, Dwight C" uniqKey="Look D" first="Dwight C." last="Look">Dwight C. Look</name><name sortKey="Mccray, Paul B Jr" sort="Mccray, Paul B Jr" uniqKey="Mccray P" first="Paul B. Jr" last="Mccray">Paul B. Jr Mccray</name><name sortKey="Mccray, Paul B Jr" sort="Mccray, Paul B Jr" uniqKey="Mccray P" first="Paul B. Jr" last="Mccray">Paul B. Jr Mccray</name><name sortKey="Mccray, Paul B Jr" sort="Mccray, Paul B Jr" uniqKey="Mccray P" first="Paul B. Jr" last="Mccray">Paul B. Jr Mccray</name><name sortKey="Ping Tan" sort="Ping Tan" uniqKey="Ping Tan" last="Ping Tan">PING TAN</name><name sortKey="Wohlford Lenane, Christine" sort="Wohlford Lenane, Christine" uniqKey="Wohlford Lenane C" first="Christine" last="Wohlford-Lenane">Christine Wohlford-Lenane</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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