Ectodomain shedding of angiotensin converting enzyme 2 in human airway epithelia.
Identifieur interne : 002B32 ( Main/Exploration ); précédent : 002B31; suivant : 002B33Ectodomain shedding of angiotensin converting enzyme 2 in human airway epithelia.
Auteurs : Hong Peng Jia [États-Unis] ; Dwight C. Look ; Ping Tan ; Lei Shi ; Melissa Hickey ; Lokesh Gakhar ; Mark C. Chappell ; Christine Wohlford-Lenane ; Paul B. MccraySource :
- American journal of physiology. Lung cellular and molecular physiology [ 1522-1504 ] ; 2009.
Descripteurs français
- KwdFr :
- Activation enzymatique, Appareil respiratoire (cytologie), Cellules épithéliales (cytologie), Cellules épithéliales (enzymologie), Humains, Lignée cellulaire, Membrane cellulaire (métabolisme), Modèles moléculaires, Peptidyl-Dipeptidase A (), Peptidyl-Dipeptidase A (métabolisme), Polarité de la cellule, Protéines mutantes (métabolisme), Pénétration virale, Solubilité, Structure tertiaire des protéines, Syndrome respiratoire aigu sévère (enzymologie), Syndrome respiratoire aigu sévère (virologie), Virus du SRAS (physiologie).
- MESH :
- cytologie : Appareil respiratoire, Cellules épithéliales.
- enzymologie : Cellules épithéliales, Syndrome respiratoire aigu sévère.
- métabolisme : Membrane cellulaire, Peptidyl-Dipeptidase A, Protéines mutantes.
- physiologie : Virus du SRAS.
- virologie : Syndrome respiratoire aigu sévère.
- Activation enzymatique, Humains, Lignée cellulaire, Modèles moléculaires, Peptidyl-Dipeptidase A, Polarité de la cellule, Pénétration virale, Solubilité, Structure tertiaire des protéines.
English descriptors
- KwdEn :
- Cell Line, Cell Membrane (metabolism), Cell Polarity, Enzyme Activation, Epithelial Cells (cytology), Epithelial Cells (enzymology), Humans, Models, Molecular, Mutant Proteins (metabolism), Peptidyl-Dipeptidase A (chemistry), Peptidyl-Dipeptidase A (metabolism), Protein Structure, Tertiary, Respiratory System (cytology), SARS Virus (physiology), Severe Acute Respiratory Syndrome (enzymology), Severe Acute Respiratory Syndrome (virology), Solubility, Virus Internalization.
- MESH :
- chemical , chemistry : Peptidyl-Dipeptidase A.
- chemical , metabolism : Mutant Proteins, Peptidyl-Dipeptidase A.
- cytology : Epithelial Cells, Respiratory System.
- enzymology : Epithelial Cells, Severe Acute Respiratory Syndrome.
- metabolism : Cell Membrane.
- physiology : SARS Virus.
- virology : Severe Acute Respiratory Syndrome.
- Cell Line, Cell Polarity, Enzyme Activation, Humans, Models, Molecular, Protein Structure, Tertiary, Solubility, Virus Internalization.
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-1beta and TNFalpha 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.
DOI: 10.1152/ajplung.00071.2009
PubMed: 19411314
Affiliations:
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Le document en format XML
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Look</name></author><author><name sortKey="Tan, Ping" sort="Tan, Ping" uniqKey="Tan P" first="Ping" last="Tan">Ping Tan</name></author><author><name sortKey="Shi, Lei" sort="Shi, Lei" uniqKey="Shi L" first="Lei" last="Shi">Lei Shi</name></author><author><name sortKey="Hickey, Melissa" sort="Hickey, Melissa" uniqKey="Hickey M" first="Melissa" last="Hickey">Melissa Hickey</name></author><author><name sortKey="Gakhar, Lokesh" sort="Gakhar, Lokesh" uniqKey="Gakhar L" first="Lokesh" last="Gakhar">Lokesh Gakhar</name></author><author><name sortKey="Chappell, Mark C" sort="Chappell, Mark C" uniqKey="Chappell M" first="Mark C" last="Chappell">Mark C. Chappell</name></author><author><name sortKey="Wohlford Lenane, Christine" sort="Wohlford Lenane, Christine" uniqKey="Wohlford Lenane C" first="Christine" last="Wohlford-Lenane">Christine Wohlford-Lenane</name></author><author><name sortKey="Mccray, Paul B" sort="Mccray, Paul B" uniqKey="Mccray P" first="Paul B" last="Mccray">Paul B. 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Look</name></author><author><name sortKey="Tan, Ping" sort="Tan, Ping" uniqKey="Tan P" first="Ping" last="Tan">Ping Tan</name></author><author><name sortKey="Shi, Lei" sort="Shi, Lei" uniqKey="Shi L" first="Lei" last="Shi">Lei Shi</name></author><author><name sortKey="Hickey, Melissa" sort="Hickey, Melissa" uniqKey="Hickey M" first="Melissa" last="Hickey">Melissa Hickey</name></author><author><name sortKey="Gakhar, Lokesh" sort="Gakhar, Lokesh" uniqKey="Gakhar L" first="Lokesh" last="Gakhar">Lokesh Gakhar</name></author><author><name sortKey="Chappell, Mark C" sort="Chappell, Mark C" uniqKey="Chappell M" first="Mark C" last="Chappell">Mark C. Chappell</name></author><author><name sortKey="Wohlford Lenane, Christine" sort="Wohlford Lenane, Christine" uniqKey="Wohlford Lenane C" first="Christine" last="Wohlford-Lenane">Christine Wohlford-Lenane</name></author><author><name sortKey="Mccray, Paul B" sort="Mccray, Paul B" uniqKey="Mccray P" first="Paul B" last="Mccray">Paul B. Mccray</name></author></analytic><series><title level="j">American journal of physiology. Lung cellular and molecular physiology</title><idno type="eISSN">1522-1504</idno><imprint><date when="2009" type="published">2009</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Cell Line</term><term>Cell Membrane (metabolism)</term><term>Cell Polarity</term><term>Enzyme Activation</term><term>Epithelial Cells (cytology)</term><term>Epithelial Cells (enzymology)</term><term>Humans</term><term>Models, Molecular</term><term>Mutant Proteins (metabolism)</term><term>Peptidyl-Dipeptidase A (chemistry)</term><term>Peptidyl-Dipeptidase A (metabolism)</term><term>Protein Structure, Tertiary</term><term>Respiratory System (cytology)</term><term>SARS Virus (physiology)</term><term>Severe Acute Respiratory Syndrome (enzymology)</term><term>Severe Acute Respiratory Syndrome (virology)</term><term>Solubility</term><term>Virus Internalization</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Activation enzymatique</term><term>Appareil respiratoire (cytologie)</term><term>Cellules épithéliales (cytologie)</term><term>Cellules épithéliales (enzymologie)</term><term>Humains</term><term>Lignée cellulaire</term><term>Membrane cellulaire (métabolisme)</term><term>Modèles moléculaires</term><term>Peptidyl-Dipeptidase A ()</term><term>Peptidyl-Dipeptidase A (métabolisme)</term><term>Polarité de la cellule</term><term>Protéines mutantes (métabolisme)</term><term>Pénétration virale</term><term>Solubilité</term><term>Structure tertiaire des protéines</term><term>Syndrome respiratoire aigu sévère (enzymologie)</term><term>Syndrome respiratoire aigu sévère (virologie)</term><term>Virus du SRAS (physiologie)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Peptidyl-Dipeptidase A</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Mutant Proteins</term><term>Peptidyl-Dipeptidase A</term></keywords><keywords scheme="MESH" qualifier="cytologie" xml:lang="fr"><term>Appareil respiratoire</term><term>Cellules épithéliales</term></keywords><keywords scheme="MESH" qualifier="cytology" xml:lang="en"><term>Epithelial Cells</term><term>Respiratory System</term></keywords><keywords scheme="MESH" qualifier="enzymologie" xml:lang="fr"><term>Cellules épithéliales</term><term>Syndrome respiratoire aigu sévère</term></keywords><keywords scheme="MESH" qualifier="enzymology" xml:lang="en"><term>Epithelial Cells</term><term>Severe Acute Respiratory Syndrome</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Cell Membrane</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Membrane cellulaire</term><term>Peptidyl-Dipeptidase A</term><term>Protéines mutantes</term></keywords><keywords scheme="MESH" qualifier="physiologie" xml:lang="fr"><term>Virus du SRAS</term></keywords><keywords scheme="MESH" qualifier="physiology" xml:lang="en"><term>SARS Virus</term></keywords><keywords scheme="MESH" qualifier="virologie" xml:lang="fr"><term>Syndrome respiratoire aigu sévère</term></keywords><keywords scheme="MESH" qualifier="virology" xml:lang="en"><term>Severe Acute Respiratory Syndrome</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Cell Line</term><term>Cell Polarity</term><term>Enzyme Activation</term><term>Humans</term><term>Models, Molecular</term><term>Protein Structure, Tertiary</term><term>Solubility</term><term>Virus Internalization</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Activation enzymatique</term><term>Humains</term><term>Lignée cellulaire</term><term>Modèles moléculaires</term><term>Peptidyl-Dipeptidase A</term><term>Polarité de la cellule</term><term>Pénétration virale</term><term>Solubilité</term><term>Structure tertiaire des protéines</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-1beta and TNFalpha 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>Iowa</li></region><settlement><li>Iowa City</li></settlement><orgName><li>Université de l'Iowa</li></orgName></list><tree><noCountry><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="Look, Dwight C" sort="Look, Dwight C" uniqKey="Look D" first="Dwight C" last="Look">Dwight C. Look</name><name sortKey="Mccray, Paul B" sort="Mccray, Paul B" uniqKey="Mccray P" first="Paul B" last="Mccray">Paul B. Mccray</name><name sortKey="Shi, Lei" sort="Shi, Lei" uniqKey="Shi L" first="Lei" last="Shi">Lei Shi</name><name sortKey="Tan, Ping" sort="Tan, Ping" uniqKey="Tan P" first="Ping" last="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></noCountry><country name="États-Unis"><region name="Iowa"><name sortKey="Jia, Hong Peng" sort="Jia, Hong Peng" uniqKey="Jia H" first="Hong Peng" last="Jia">Hong Peng Jia</name></region></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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