Chemical Genomics Identifies the PERK-Mediated Unfolded Protein Stress Response as a Cellular Target for Influenza Virus Inhibition.
Identifieur interne : 000B91 ( Main/Exploration ); précédent : 000B90; suivant : 000B92Chemical Genomics Identifies the PERK-Mediated Unfolded Protein Stress Response as a Cellular Target for Influenza Virus Inhibition.
Auteurs : Sara Landeras-Bueno [Espagne] ; Yolanda Fernández [Espagne] ; Ana Falc N [Espagne] ; Juan Carlos Oliveros [Espagne] ; Juan Ortín [Espagne]Source :
- mBio [ 2150-7511 ] ; 2016.
Descripteurs français
- KwdFr :
- Acétates (pharmacologie), Grippe humaine (enzymologie), Grippe humaine (génétique), Grippe humaine (physiopathologie), Grippe humaine (virologie), Humains, Phosphorylation, Protéines virales (génétique), Protéines virales (métabolisme), Quinoléines (pharmacologie), Réplication virale (), Réponse aux protéines mal repliées (), Virus de la grippe A (), Virus de la grippe A (génétique), Virus de la grippe A (physiologie), eIF-2 Kinase (génétique), eIF-2 Kinase (métabolisme).
- MESH :
- enzymologie : Grippe humaine.
- génétique : Grippe humaine, Protéines virales, Virus de la grippe A, eIF-2 Kinase.
- métabolisme : Protéines virales, eIF-2 Kinase.
- pharmacologie : Acétates, Quinoléines.
- physiologie : Virus de la grippe A.
- physiopathologie : Grippe humaine.
- virologie : Grippe humaine.
- Humains, Phosphorylation, Réplication virale, Réponse aux protéines mal repliées, Virus de la grippe A.
English descriptors
- KwdEn :
- Acetates (pharmacology), Humans, Influenza A virus (drug effects), Influenza A virus (genetics), Influenza A virus (physiology), Influenza, Human (enzymology), Influenza, Human (genetics), Influenza, Human (physiopathology), Influenza, Human (virology), Phosphorylation, Quinolines (pharmacology), Unfolded Protein Response (drug effects), Viral Proteins (genetics), Viral Proteins (metabolism), Virus Replication (drug effects), eIF-2 Kinase (genetics), eIF-2 Kinase (metabolism).
- MESH :
- chemical , genetics : Viral Proteins, eIF-2 Kinase.
- chemical , metabolism : Viral Proteins, eIF-2 Kinase.
- chemical , pharmacology : Acetates, Quinolines.
- drug effects : Influenza A virus, Unfolded Protein Response, Virus Replication.
- enzymology : Influenza, Human.
- genetics : Influenza A virus, Influenza, Human.
- physiology : Influenza A virus.
- physiopathology : Influenza, Human.
- virology : Influenza, Human.
- Humans, Phosphorylation.
Abstract
Influenza A viruses generate annual epidemics and occasional pandemics of respiratory disease with important consequences for human health and the economy. Therefore, a large effort has been devoted to the development of new anti-influenza virus drugs directed to viral targets, as well as to the identification of cellular targets amenable to anti-influenza virus therapy. Here we have addressed the identification of such potential cellular targets by screening collections of drugs approved for human use. We reasoned that screening with a green fluorescent protein-based recombinant replicon system would identify cellular targets involved in virus transcription/replication and/or gene expression and hence address an early stage of virus infection. By using such a strategy, we identified Montelukast (MK) as an inhibitor of virus multiplication. MK inhibited virus gene expression but did not alter viral RNA synthesis in vitro or viral RNA accumulation in vivo The low selectivity index of MK prevented its use as an antiviral, but it was sufficient to identify a new cellular pathway suitable for anti-influenza virus intervention. By deep sequencing of RNA isolated from mock- and virus-infected human cells, treated with MK or left untreated, we showed that it stimulates the PERK-mediated unfolded protein stress response. The phosphorylation of PERK was partly inhibited in virus-infected cells but stimulated in MK-treated cells. Accordingly, pharmacological inhibition of PERK phosphorylation led to increased viral gene expression, while inhibition of PERK phosphatase reduced viral protein synthesis. These results suggest the PERK-mediated unfolded protein response as a potential cellular target to modulate influenza virus infection.
DOI: 10.1128/mBio.00085-16
PubMed: 27094326
Affiliations:
Links toward previous steps (curation, corpus...)
- to stream PubMed, to step Corpus: 000367
- to stream PubMed, to step Curation: 000366
- to stream PubMed, to step Checkpoint: 000376
- to stream Ncbi, to step Merge: 000788
- to stream Ncbi, to step Curation: 000788
- to stream Ncbi, to step Checkpoint: 000788
- to stream Main, to step Merge: 000B91
- to stream Main, to step Curation: 000B91
Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Chemical Genomics Identifies the PERK-Mediated Unfolded Protein Stress Response as a Cellular Target for Influenza Virus Inhibition.</title><author><name sortKey="Landeras Bueno, Sara" sort="Landeras Bueno, Sara" uniqKey="Landeras Bueno S" first="Sara" last="Landeras-Bueno">Sara Landeras-Bueno</name><affiliation wicri:level="3"><nlm:affiliation>Departamento de Biología Molecular y Celular, Centro Nacional de Biotecnología (CSIC), Madrid, Spain Ciber de Enfermedades Respiratorias (ISCIII), Madrid, Spain.</nlm:affiliation><country xml:lang="fr">Espagne</country><wicri:regionArea>Departamento de Biología Molecular y Celular, Centro Nacional de Biotecnología (CSIC), Madrid, Spain Ciber de Enfermedades Respiratorias (ISCIII), Madrid</wicri:regionArea><placeName><settlement type="city">Madrid</settlement><region nuts="2" type="region">Communauté de Madrid</region></placeName></affiliation></author><author><name sortKey="Fernandez, Yolanda" sort="Fernandez, Yolanda" uniqKey="Fernandez Y" first="Yolanda" last="Fernández">Yolanda Fernández</name><affiliation wicri:level="3"><nlm:affiliation>Departamento de Biología Molecular y Celular, Centro Nacional de Biotecnología (CSIC), Madrid, Spain Ciber de Enfermedades Respiratorias (ISCIII), Madrid, Spain.</nlm:affiliation><country xml:lang="fr">Espagne</country><wicri:regionArea>Departamento de Biología Molecular y Celular, Centro Nacional de Biotecnología (CSIC), Madrid, Spain Ciber de Enfermedades Respiratorias (ISCIII), Madrid</wicri:regionArea><placeName><settlement type="city">Madrid</settlement><region nuts="2" type="region">Communauté de Madrid</region></placeName></affiliation></author><author><name sortKey="Falc N, Ana" sort="Falc N, Ana" uniqKey="Falc N A" first="Ana" last="Falc N">Ana Falc N</name><affiliation wicri:level="3"><nlm:affiliation>Departamento de Biología Molecular y Celular, Centro Nacional de Biotecnología (CSIC), Madrid, Spain Ciber de Enfermedades Respiratorias (ISCIII), Madrid, Spain.</nlm:affiliation><country xml:lang="fr">Espagne</country><wicri:regionArea>Departamento de Biología Molecular y Celular, Centro Nacional de Biotecnología (CSIC), Madrid, Spain Ciber de Enfermedades Respiratorias (ISCIII), Madrid</wicri:regionArea><placeName><settlement type="city">Madrid</settlement><region nuts="2" type="region">Communauté de Madrid</region></placeName></affiliation></author><author><name sortKey="Oliveros, Juan Carlos" sort="Oliveros, Juan Carlos" uniqKey="Oliveros J" first="Juan Carlos" last="Oliveros">Juan Carlos Oliveros</name><affiliation wicri:level="3"><nlm:affiliation>Servicio de Genómica Computacional, Centro Nacional de Biotecnología (CSIC), Madrid, Spain.</nlm:affiliation><country xml:lang="fr">Espagne</country><wicri:regionArea>Servicio de Genómica Computacional, Centro Nacional de Biotecnología (CSIC), Madrid</wicri:regionArea><placeName><settlement type="city">Madrid</settlement><region nuts="2" type="region">Communauté de Madrid</region></placeName></affiliation></author><author><name sortKey="Ortin, Juan" sort="Ortin, Juan" uniqKey="Ortin J" first="Juan" last="Ortín">Juan Ortín</name><affiliation wicri:level="3"><nlm:affiliation>Departamento de Biología Molecular y Celular, Centro Nacional de Biotecnología (CSIC), Madrid, Spain Ciber de Enfermedades Respiratorias (ISCIII), Madrid, Spain jortin@cnb.csic.es.</nlm:affiliation><country wicri:rule="url">Espagne</country><wicri:regionArea>Departamento de Biología Molecular y Celular, Centro Nacional de Biotecnología (CSIC), Madrid, Spain Ciber de Enfermedades Respiratorias (ISCIII), Madrid</wicri:regionArea><placeName><settlement type="city">Madrid</settlement><region nuts="2" type="region">Communauté de Madrid</region></placeName></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2016">2016</date><idno type="RBID">pubmed:27094326</idno><idno type="pmid">27094326</idno><idno type="doi">10.1128/mBio.00085-16</idno><idno type="wicri:Area/PubMed/Corpus">000367</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">000367</idno><idno type="wicri:Area/PubMed/Curation">000366</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Curation">000366</idno><idno type="wicri:Area/PubMed/Checkpoint">000376</idno><idno type="wicri:explorRef" wicri:stream="Checkpoint" wicri:step="PubMed">000376</idno><idno type="wicri:Area/Ncbi/Merge">000788</idno><idno type="wicri:Area/Ncbi/Curation">000788</idno><idno type="wicri:Area/Ncbi/Checkpoint">000788</idno><idno type="wicri:Area/Main/Merge">000B91</idno><idno type="wicri:Area/Main/Curation">000B91</idno><idno type="wicri:Area/Main/Exploration">000B91</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">Chemical Genomics Identifies the PERK-Mediated Unfolded Protein Stress Response as a Cellular Target for Influenza Virus Inhibition.</title><author><name sortKey="Landeras Bueno, Sara" sort="Landeras Bueno, Sara" uniqKey="Landeras Bueno S" first="Sara" last="Landeras-Bueno">Sara Landeras-Bueno</name><affiliation wicri:level="3"><nlm:affiliation>Departamento de Biología Molecular y Celular, Centro Nacional de Biotecnología (CSIC), Madrid, Spain Ciber de Enfermedades Respiratorias (ISCIII), Madrid, Spain.</nlm:affiliation><country xml:lang="fr">Espagne</country><wicri:regionArea>Departamento de Biología Molecular y Celular, Centro Nacional de Biotecnología (CSIC), Madrid, Spain Ciber de Enfermedades Respiratorias (ISCIII), Madrid</wicri:regionArea><placeName><settlement type="city">Madrid</settlement><region nuts="2" type="region">Communauté de Madrid</region></placeName></affiliation></author><author><name sortKey="Fernandez, Yolanda" sort="Fernandez, Yolanda" uniqKey="Fernandez Y" first="Yolanda" last="Fernández">Yolanda Fernández</name><affiliation wicri:level="3"><nlm:affiliation>Departamento de Biología Molecular y Celular, Centro Nacional de Biotecnología (CSIC), Madrid, Spain Ciber de Enfermedades Respiratorias (ISCIII), Madrid, Spain.</nlm:affiliation><country xml:lang="fr">Espagne</country><wicri:regionArea>Departamento de Biología Molecular y Celular, Centro Nacional de Biotecnología (CSIC), Madrid, Spain Ciber de Enfermedades Respiratorias (ISCIII), Madrid</wicri:regionArea><placeName><settlement type="city">Madrid</settlement><region nuts="2" type="region">Communauté de Madrid</region></placeName></affiliation></author><author><name sortKey="Falc N, Ana" sort="Falc N, Ana" uniqKey="Falc N A" first="Ana" last="Falc N">Ana Falc N</name><affiliation wicri:level="3"><nlm:affiliation>Departamento de Biología Molecular y Celular, Centro Nacional de Biotecnología (CSIC), Madrid, Spain Ciber de Enfermedades Respiratorias (ISCIII), Madrid, Spain.</nlm:affiliation><country xml:lang="fr">Espagne</country><wicri:regionArea>Departamento de Biología Molecular y Celular, Centro Nacional de Biotecnología (CSIC), Madrid, Spain Ciber de Enfermedades Respiratorias (ISCIII), Madrid</wicri:regionArea><placeName><settlement type="city">Madrid</settlement><region nuts="2" type="region">Communauté de Madrid</region></placeName></affiliation></author><author><name sortKey="Oliveros, Juan Carlos" sort="Oliveros, Juan Carlos" uniqKey="Oliveros J" first="Juan Carlos" last="Oliveros">Juan Carlos Oliveros</name><affiliation wicri:level="3"><nlm:affiliation>Servicio de Genómica Computacional, Centro Nacional de Biotecnología (CSIC), Madrid, Spain.</nlm:affiliation><country xml:lang="fr">Espagne</country><wicri:regionArea>Servicio de Genómica Computacional, Centro Nacional de Biotecnología (CSIC), Madrid</wicri:regionArea><placeName><settlement type="city">Madrid</settlement><region nuts="2" type="region">Communauté de Madrid</region></placeName></affiliation></author><author><name sortKey="Ortin, Juan" sort="Ortin, Juan" uniqKey="Ortin J" first="Juan" last="Ortín">Juan Ortín</name><affiliation wicri:level="3"><nlm:affiliation>Departamento de Biología Molecular y Celular, Centro Nacional de Biotecnología (CSIC), Madrid, Spain Ciber de Enfermedades Respiratorias (ISCIII), Madrid, Spain jortin@cnb.csic.es.</nlm:affiliation><country wicri:rule="url">Espagne</country><wicri:regionArea>Departamento de Biología Molecular y Celular, Centro Nacional de Biotecnología (CSIC), Madrid, Spain Ciber de Enfermedades Respiratorias (ISCIII), Madrid</wicri:regionArea><placeName><settlement type="city">Madrid</settlement><region nuts="2" type="region">Communauté de Madrid</region></placeName></affiliation></author></analytic><series><title level="j">mBio</title><idno type="eISSN">2150-7511</idno><imprint><date when="2016" type="published">2016</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Acetates (pharmacology)</term><term>Humans</term><term>Influenza A virus (drug effects)</term><term>Influenza A virus (genetics)</term><term>Influenza A virus (physiology)</term><term>Influenza, Human (enzymology)</term><term>Influenza, Human (genetics)</term><term>Influenza, Human (physiopathology)</term><term>Influenza, Human (virology)</term><term>Phosphorylation</term><term>Quinolines (pharmacology)</term><term>Unfolded Protein Response (drug effects)</term><term>Viral Proteins (genetics)</term><term>Viral Proteins (metabolism)</term><term>Virus Replication (drug effects)</term><term>eIF-2 Kinase (genetics)</term><term>eIF-2 Kinase (metabolism)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Acétates (pharmacologie)</term><term>Grippe humaine (enzymologie)</term><term>Grippe humaine (génétique)</term><term>Grippe humaine (physiopathologie)</term><term>Grippe humaine (virologie)</term><term>Humains</term><term>Phosphorylation</term><term>Protéines virales (génétique)</term><term>Protéines virales (métabolisme)</term><term>Quinoléines (pharmacologie)</term><term>Réplication virale ()</term><term>Réponse aux protéines mal repliées ()</term><term>Virus de la grippe A ()</term><term>Virus de la grippe A (génétique)</term><term>Virus de la grippe A (physiologie)</term><term>eIF-2 Kinase (génétique)</term><term>eIF-2 Kinase (métabolisme)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Viral Proteins</term><term>eIF-2 Kinase</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Viral Proteins</term><term>eIF-2 Kinase</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Acetates</term><term>Quinolines</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Influenza A virus</term><term>Unfolded Protein Response</term><term>Virus Replication</term></keywords><keywords scheme="MESH" qualifier="enzymologie" xml:lang="fr"><term>Grippe humaine</term></keywords><keywords scheme="MESH" qualifier="enzymology" xml:lang="en"><term>Influenza, Human</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Influenza A virus</term><term>Influenza, Human</term></keywords><keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Grippe humaine</term><term>Protéines virales</term><term>Virus de la grippe A</term><term>eIF-2 Kinase</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Protéines virales</term><term>eIF-2 Kinase</term></keywords><keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Acétates</term><term>Quinoléines</term></keywords><keywords scheme="MESH" qualifier="physiologie" xml:lang="fr"><term>Virus de la grippe A</term></keywords><keywords scheme="MESH" qualifier="physiology" xml:lang="en"><term>Influenza A virus</term></keywords><keywords scheme="MESH" qualifier="physiopathologie" xml:lang="fr"><term>Grippe humaine</term></keywords><keywords scheme="MESH" qualifier="physiopathology" xml:lang="en"><term>Influenza, Human</term></keywords><keywords scheme="MESH" qualifier="virologie" xml:lang="fr"><term>Grippe humaine</term></keywords><keywords scheme="MESH" qualifier="virology" xml:lang="en"><term>Influenza, Human</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Humans</term><term>Phosphorylation</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Humains</term><term>Phosphorylation</term><term>Réplication virale</term><term>Réponse aux protéines mal repliées</term><term>Virus de la grippe A</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Influenza A viruses generate annual epidemics and occasional pandemics of respiratory disease with important consequences for human health and the economy. Therefore, a large effort has been devoted to the development of new anti-influenza virus drugs directed to viral targets, as well as to the identification of cellular targets amenable to anti-influenza virus therapy. Here we have addressed the identification of such potential cellular targets by screening collections of drugs approved for human use. We reasoned that screening with a green fluorescent protein-based recombinant replicon system would identify cellular targets involved in virus transcription/replication and/or gene expression and hence address an early stage of virus infection. By using such a strategy, we identified Montelukast (MK) as an inhibitor of virus multiplication. MK inhibited virus gene expression but did not alter viral RNA synthesis in vitro or viral RNA accumulation in vivo The low selectivity index of MK prevented its use as an antiviral, but it was sufficient to identify a new cellular pathway suitable for anti-influenza virus intervention. By deep sequencing of RNA isolated from mock- and virus-infected human cells, treated with MK or left untreated, we showed that it stimulates the PERK-mediated unfolded protein stress response. The phosphorylation of PERK was partly inhibited in virus-infected cells but stimulated in MK-treated cells. Accordingly, pharmacological inhibition of PERK phosphorylation led to increased viral gene expression, while inhibition of PERK phosphatase reduced viral protein synthesis. These results suggest the PERK-mediated unfolded protein response as a potential cellular target to modulate influenza virus infection.</div></front></TEI><affiliations><list><country><li>Espagne</li></country><region><li>Communauté de Madrid</li></region><settlement><li>Madrid</li></settlement></list><tree><country name="Espagne"><region name="Communauté de Madrid"><name sortKey="Landeras Bueno, Sara" sort="Landeras Bueno, Sara" uniqKey="Landeras Bueno S" first="Sara" last="Landeras-Bueno">Sara Landeras-Bueno</name></region><name sortKey="Falc N, Ana" sort="Falc N, Ana" uniqKey="Falc N A" first="Ana" last="Falc N">Ana Falc N</name><name sortKey="Fernandez, Yolanda" sort="Fernandez, Yolanda" uniqKey="Fernandez Y" first="Yolanda" last="Fernández">Yolanda Fernández</name><name sortKey="Oliveros, Juan Carlos" sort="Oliveros, Juan Carlos" uniqKey="Oliveros J" first="Juan Carlos" last="Oliveros">Juan Carlos Oliveros</name><name sortKey="Ortin, Juan" sort="Ortin, Juan" uniqKey="Ortin J" first="Juan" last="Ortín">Juan Ortín</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
EXPLOR_STEP=$WICRI_ROOT/Sante/explor/StressCovidV1/Data/Main/Exploration
HfdSelect -h $EXPLOR_STEP/biblio.hfd -nk 000B91 | SxmlIndent | more
Ou
HfdSelect -h $EXPLOR_AREA/Data/Main/Exploration/biblio.hfd -nk 000B91 | SxmlIndent | more
Pour mettre un lien sur cette page dans le réseau Wicri
{{Explor lien
|wiki= Sante
|area= StressCovidV1
|flux= Main
|étape= Exploration
|type= RBID
|clé= pubmed:27094326
|texte= Chemical Genomics Identifies the PERK-Mediated Unfolded Protein Stress Response as a Cellular Target for Influenza Virus Inhibition.
}}
Pour générer des pages wiki
HfdIndexSelect -h $EXPLOR_AREA/Data/Main/Exploration/RBID.i -Sk "pubmed:27094326" \
| HfdSelect -Kh $EXPLOR_AREA/Data/Main/Exploration/biblio.hfd \
| NlmPubMed2Wicri -a StressCovidV1
| This area was generated with Dilib version V0.6.33. |  |