TMPRSS2 and ADAM17 cleave ACE2 differentially and only proteolysis by TMPRSS2 augments entry driven by the severe acute respiratory syndrome coronavirus spike protein.
Identifieur interne : 001554 ( Main/Exploration ); précédent : 001553; suivant : 001555TMPRSS2 and ADAM17 cleave ACE2 differentially and only proteolysis by TMPRSS2 augments entry driven by the severe acute respiratory syndrome coronavirus spike protein.
Auteurs : Adeline Heurich [Allemagne] ; Heike Hofmann-Winkler ; Stefanie Gierer ; Thomas Liepold ; Olaf Jahn ; Stefan PöhlmannSource :
- Journal of virology [ 1098-5514 ] ; 2014.
Descripteurs français
- KwdFr :
- Glycoprotéine de spicule des coronavirus (génétique), Glycoprotéine de spicule des coronavirus (métabolisme), Humains, Lignée cellulaire, Maturation post-traductionnelle des protéines, Motifs d'acides aminés, Peptidyl-Dipeptidase A (), Peptidyl-Dipeptidase A (génétique), Peptidyl-Dipeptidase A (métabolisme), Protéine ADAM17, Protéines ADAM (génétique), Protéines ADAM (métabolisme), Protéolyse, Pénétration virale, Récepteurs viraux (génétique), Récepteurs viraux (métabolisme), Serine endopeptidases (génétique), Serine endopeptidases (métabolisme), Syndrome respiratoire aigu sévère (enzymologie), Syndrome respiratoire aigu sévère (génétique), Syndrome respiratoire aigu sévère (métabolisme), Syndrome respiratoire aigu sévère (virologie), Virus du SRAS (génétique), Virus du SRAS (physiologie).
- MESH :
- enzymologie : Syndrome respiratoire aigu sévère.
- génétique : Glycoprotéine de spicule des coronavirus, Peptidyl-Dipeptidase A, Protéines ADAM, Récepteurs viraux, Serine endopeptidases, Syndrome respiratoire aigu sévère, Virus du SRAS.
- métabolisme : Glycoprotéine de spicule des coronavirus, Peptidyl-Dipeptidase A, Protéines ADAM, Récepteurs viraux, Serine endopeptidases, Syndrome respiratoire aigu sévère.
- physiologie : Virus du SRAS.
- virologie : Syndrome respiratoire aigu sévère.
- Humains, Lignée cellulaire, Maturation post-traductionnelle des protéines, Motifs d'acides aminés, Peptidyl-Dipeptidase A, Protéine ADAM17, Protéolyse, Pénétration virale.
English descriptors
- KwdEn :
- ADAM Proteins (genetics), ADAM Proteins (metabolism), ADAM17 Protein, Amino Acid Motifs, Cell Line, Humans, Peptidyl-Dipeptidase A (chemistry), Peptidyl-Dipeptidase A (genetics), Peptidyl-Dipeptidase A (metabolism), Protein Processing, Post-Translational, Proteolysis, Receptors, Virus (genetics), Receptors, Virus (metabolism), SARS Virus (genetics), SARS Virus (physiology), Serine Endopeptidases (genetics), Serine Endopeptidases (metabolism), Severe Acute Respiratory Syndrome (enzymology), Severe Acute Respiratory Syndrome (genetics), Severe Acute Respiratory Syndrome (metabolism), Severe Acute Respiratory Syndrome (virology), Spike Glycoprotein, Coronavirus (genetics), Spike Glycoprotein, Coronavirus (metabolism), Virus Internalization.
- MESH :
- chemical , chemistry : Peptidyl-Dipeptidase A.
- chemical , genetics : ADAM Proteins, Peptidyl-Dipeptidase A, Receptors, Virus, Serine Endopeptidases, Spike Glycoprotein, Coronavirus.
- chemical , metabolism : ADAM Proteins, Peptidyl-Dipeptidase A, Receptors, Virus, Serine Endopeptidases, Spike Glycoprotein, Coronavirus.
- chemical : ADAM17 Protein.
- enzymology : Severe Acute Respiratory Syndrome.
- genetics : SARS Virus, Severe Acute Respiratory Syndrome.
- metabolism : Severe Acute Respiratory Syndrome.
- physiology : SARS Virus.
- virology : Severe Acute Respiratory Syndrome.
- Amino Acid Motifs, Cell Line, Humans, Protein Processing, Post-Translational, Proteolysis, Virus Internalization.
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.
DOI: 10.1128/JVI.02202-13
PubMed: 24227843
Affiliations:
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Le document en format XML
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Internalization</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Humains</term><term>Lignée cellulaire</term><term>Maturation post-traductionnelle des protéines</term><term>Motifs d'acides aminés</term><term>Peptidyl-Dipeptidase A</term><term>Protéine ADAM17</term><term>Protéolyse</term><term>Pénétration virale</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">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. </div></front></TEI><affiliations><list><country><li>Allemagne</li></country><region><li>Basse-Saxe</li></region><settlement><li>Göttingen</li></settlement></list><tree><noCountry><name sortKey="Gierer, Stefanie" sort="Gierer, Stefanie" uniqKey="Gierer S" first="Stefanie" last="Gierer">Stefanie Gierer</name><name sortKey="Hofmann Winkler, Heike" sort="Hofmann Winkler, Heike" uniqKey="Hofmann Winkler H" first="Heike" last="Hofmann-Winkler">Heike Hofmann-Winkler</name><name sortKey="Jahn, Olaf" sort="Jahn, Olaf" uniqKey="Jahn O" first="Olaf" last="Jahn">Olaf Jahn</name><name sortKey="Liepold, Thomas" sort="Liepold, Thomas" uniqKey="Liepold T" first="Thomas" last="Liepold">Thomas Liepold</name><name sortKey="Pohlmann, Stefan" sort="Pohlmann, Stefan" uniqKey="Pohlmann S" first="Stefan" last="Pöhlmann">Stefan Pöhlmann</name></noCountry><country name="Allemagne"><region name="Basse-Saxe"><name sortKey="Heurich, Adeline" sort="Heurich, Adeline" uniqKey="Heurich A" first="Adeline" last="Heurich">Adeline Heurich</name></region></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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