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Aminoacyl-tRNA synthetase inhibition activates a pathway that branches from the canonical amino acid response in mammalian cells.

Identifieur interne : 000153 ( Main/Exploration ); précédent : 000152; suivant : 000154

Aminoacyl-tRNA synthetase inhibition activates a pathway that branches from the canonical amino acid response in mammalian cells.

Auteurs : Yeonjin Kim [États-Unis] ; Mark S. Sundrud [États-Unis] ; Changqian Zhou [États-Unis] ; Maja Edenius [États-Unis] ; Davide Zocco [États-Unis] ; Kristen Powers [États-Unis] ; Miao Zhang [États-Unis] ; Ralph Mazitschek [États-Unis] ; Anjana Rao [États-Unis] ; Chang-Yeol Yeo [Corée du Sud] ; Erika H. Noss [États-Unis] ; Michael B. Brenner [États-Unis] ; Malcolm Whitman [États-Unis] ; Tracy L. Keller [États-Unis]

Source :

RBID : pubmed:32253314

Descripteurs français

English descriptors

Abstract

Signaling pathways that sense amino acid abundance are integral to tissue homeostasis and cellular defense. Our laboratory has previously shown that halofuginone (HF) inhibits the prolyl-tRNA synthetase catalytic activity of glutamyl-prolyl-tRNA synthetase (EPRS), thereby activating the amino acid response (AAR). We now show that HF treatment selectively inhibits inflammatory responses in diverse cell types and that these therapeutic benefits occur in cells that lack GCN2, the signature effector of the AAR. Depletion of arginine, histidine, or lysine from cultured fibroblast-like synoviocytes recapitulates key aspects of HF treatment, without utilizing GCN2 or mammalian target of rapamycin complex 1 pathway signaling. Like HF, the threonyl-tRNA synthetase inhibitor borrelidin suppresses the induction of tissue remodeling and inflammatory mediators in cytokine-stimulated fibroblast-like synoviocytes without GCN2, but both aminoacyl-tRNA synthetase (aaRS) inhibitors are sensitive to the removal of GCN1. GCN1, an upstream component of the AAR pathway, binds to ribosomes and is required for GCN2 activation. These observations indicate that aaRS inhibitors, like HF, can modulate inflammatory response without the AAR/GCN2 signaling cassette, and that GCN1 has a role that is distinct from its activation of GCN2. We propose that GCN1 participates in a previously unrecognized amino acid sensor pathway that branches from the canonical AAR.

DOI: 10.1073/pnas.1913788117
PubMed: 32253314
PubMed Central: PMC7183223


Affiliations:


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Le document en format XML

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<term>Amino Acids (metabolism)</term>
<term>Amino Acyl-tRNA Synthetases (antagonists & inhibitors)</term>
<term>Amino Acyl-tRNA Synthetases (metabolism)</term>
<term>Animals (MeSH)</term>
<term>Anti-Inflammatory Agents (pharmacology)</term>
<term>Anti-Inflammatory Agents (therapeutic use)</term>
<term>Arthritis, Rheumatoid (drug therapy)</term>
<term>Arthritis, Rheumatoid (immunology)</term>
<term>Arthritis, Rheumatoid (pathology)</term>
<term>Arthritis, Rheumatoid (surgery)</term>
<term>Cell Line (MeSH)</term>
<term>Fibroblasts (MeSH)</term>
<term>Gene Knockdown Techniques (MeSH)</term>
<term>Human Umbilical Vein Endothelial Cells (MeSH)</term>
<term>Humans (MeSH)</term>
<term>Lung (cytology)</term>
<term>Mechanistic Target of Rapamycin Complex 1 (metabolism)</term>
<term>Mice (MeSH)</term>
<term>Mice, Knockout (MeSH)</term>
<term>Piperidines (pharmacology)</term>
<term>Piperidines (therapeutic use)</term>
<term>Primary Cell Culture (MeSH)</term>
<term>Protein-Serine-Threonine Kinases (genetics)</term>
<term>Protein-Serine-Threonine Kinases (metabolism)</term>
<term>Quinazolinones (pharmacology)</term>
<term>Quinazolinones (therapeutic use)</term>
<term>RNA-Binding Proteins (genetics)</term>
<term>RNA-Binding Proteins (metabolism)</term>
<term>RNA-Seq (MeSH)</term>
<term>Signal Transduction (drug effects)</term>
<term>Signal Transduction (immunology)</term>
<term>Synovial Membrane (cytology)</term>
<term>Synovial Membrane (pathology)</term>
<term>Synoviocytes (MeSH)</term>
<term>Trans-Activators (genetics)</term>
<term>Trans-Activators (metabolism)</term>
</keywords>
<keywords scheme="KwdFr" xml:lang="fr">
<term>Acides aminés (métabolisme)</term>
<term>Amino acyl-tRNA synthetases (antagonistes et inhibiteurs)</term>
<term>Amino acyl-tRNA synthetases (métabolisme)</term>
<term>Animaux (MeSH)</term>
<term>Anti-inflammatoires (pharmacologie)</term>
<term>Anti-inflammatoires (usage thérapeutique)</term>
<term>Cellules endothéliales de la veine ombilicale humaine (MeSH)</term>
<term>Cellules synoviales (MeSH)</term>
<term>Complexe-1 cible mécanistique de la rapamycine (métabolisme)</term>
<term>Culture de cellules primaires (MeSH)</term>
<term>Fibroblastes (MeSH)</term>
<term>Humains (MeSH)</term>
<term>Lignée cellulaire (MeSH)</term>
<term>Membrane synoviale (anatomopathologie)</term>
<term>Membrane synoviale (cytologie)</term>
<term>Pipéridines (pharmacologie)</term>
<term>Pipéridines (usage thérapeutique)</term>
<term>Polyarthrite rhumatoïde (anatomopathologie)</term>
<term>Polyarthrite rhumatoïde (chirurgie)</term>
<term>Polyarthrite rhumatoïde (immunologie)</term>
<term>Polyarthrite rhumatoïde (traitement médicamenteux)</term>
<term>Poumon (cytologie)</term>
<term>Protein-Serine-Threonine Kinases (génétique)</term>
<term>Protein-Serine-Threonine Kinases (métabolisme)</term>
<term>Protéines de liaison à l'ARN (génétique)</term>
<term>Protéines de liaison à l'ARN (métabolisme)</term>
<term>Quinazolinones (pharmacologie)</term>
<term>Quinazolinones (usage thérapeutique)</term>
<term>Souris (MeSH)</term>
<term>Souris knockout (MeSH)</term>
<term>Techniques de knock-down de gènes (MeSH)</term>
<term>Transactivateurs (génétique)</term>
<term>Transactivateurs (métabolisme)</term>
<term>Transduction du signal (effets des médicaments et des substances chimiques)</term>
<term>Transduction du signal (immunologie)</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="antagonists & inhibitors" xml:lang="en">
<term>Amino Acyl-tRNA Synthetases</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en">
<term>Protein-Serine-Threonine Kinases</term>
<term>RNA-Binding Proteins</term>
<term>Trans-Activators</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en">
<term>Amino Acids</term>
<term>Amino Acyl-tRNA Synthetases</term>
<term>Mechanistic Target of Rapamycin Complex 1</term>
<term>Protein-Serine-Threonine Kinases</term>
<term>RNA-Binding Proteins</term>
<term>Trans-Activators</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en">
<term>Anti-Inflammatory Agents</term>
<term>Piperidines</term>
<term>Quinazolinones</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="therapeutic use" xml:lang="en">
<term>Anti-Inflammatory Agents</term>
<term>Piperidines</term>
<term>Quinazolinones</term>
</keywords>
<keywords scheme="MESH" qualifier="anatomopathologie" xml:lang="fr">
<term>Membrane synoviale</term>
<term>Polyarthrite rhumatoïde</term>
</keywords>
<keywords scheme="MESH" qualifier="antagonistes et inhibiteurs" xml:lang="fr">
<term>Amino acyl-tRNA synthetases</term>
</keywords>
<keywords scheme="MESH" qualifier="chirurgie" xml:lang="fr">
<term>Polyarthrite rhumatoïde</term>
</keywords>
<keywords scheme="MESH" qualifier="cytologie" xml:lang="fr">
<term>Membrane synoviale</term>
<term>Poumon</term>
</keywords>
<keywords scheme="MESH" qualifier="cytology" xml:lang="en">
<term>Lung</term>
<term>Synovial Membrane</term>
</keywords>
<keywords scheme="MESH" qualifier="drug effects" xml:lang="en">
<term>Signal Transduction</term>
</keywords>
<keywords scheme="MESH" qualifier="drug therapy" xml:lang="en">
<term>Arthritis, Rheumatoid</term>
</keywords>
<keywords scheme="MESH" qualifier="effets des médicaments et des substances chimiques" xml:lang="fr">
<term>Transduction du signal</term>
</keywords>
<keywords scheme="MESH" qualifier="génétique" xml:lang="fr">
<term>Protein-Serine-Threonine Kinases</term>
<term>Protéines de liaison à l'ARN</term>
<term>Transactivateurs</term>
</keywords>
<keywords scheme="MESH" qualifier="immunologie" xml:lang="fr">
<term>Polyarthrite rhumatoïde</term>
<term>Transduction du signal</term>
</keywords>
<keywords scheme="MESH" qualifier="immunology" xml:lang="en">
<term>Arthritis, Rheumatoid</term>
<term>Signal Transduction</term>
</keywords>
<keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr">
<term>Acides aminés</term>
<term>Amino acyl-tRNA synthetases</term>
<term>Complexe-1 cible mécanistique de la rapamycine</term>
<term>Protein-Serine-Threonine Kinases</term>
<term>Protéines de liaison à l'ARN</term>
<term>Transactivateurs</term>
</keywords>
<keywords scheme="MESH" qualifier="pathology" xml:lang="en">
<term>Arthritis, Rheumatoid</term>
<term>Synovial Membrane</term>
</keywords>
<keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr">
<term>Anti-inflammatoires</term>
<term>Pipéridines</term>
<term>Quinazolinones</term>
</keywords>
<keywords scheme="MESH" qualifier="surgery" xml:lang="en">
<term>Arthritis, Rheumatoid</term>
</keywords>
<keywords scheme="MESH" qualifier="traitement médicamenteux" xml:lang="fr">
<term>Polyarthrite rhumatoïde</term>
</keywords>
<keywords scheme="MESH" qualifier="usage thérapeutique" xml:lang="fr">
<term>Anti-inflammatoires</term>
<term>Pipéridines</term>
<term>Quinazolinones</term>
</keywords>
<keywords scheme="MESH" xml:lang="en">
<term>Animals</term>
<term>Cell Line</term>
<term>Fibroblasts</term>
<term>Gene Knockdown Techniques</term>
<term>Human Umbilical Vein Endothelial Cells</term>
<term>Humans</term>
<term>Mice</term>
<term>Mice, Knockout</term>
<term>Primary Cell Culture</term>
<term>RNA-Seq</term>
<term>Synoviocytes</term>
</keywords>
<keywords scheme="MESH" xml:lang="fr">
<term>Animaux</term>
<term>Cellules endothéliales de la veine ombilicale humaine</term>
<term>Cellules synoviales</term>
<term>Culture de cellules primaires</term>
<term>Fibroblastes</term>
<term>Humains</term>
<term>Lignée cellulaire</term>
<term>Souris</term>
<term>Souris knockout</term>
<term>Techniques de knock-down de gènes</term>
</keywords>
</textClass>
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<front>
<div type="abstract" xml:lang="en">Signaling pathways that sense amino acid abundance are integral to tissue homeostasis and cellular defense. Our laboratory has previously shown that halofuginone (HF) inhibits the prolyl-tRNA synthetase catalytic activity of glutamyl-prolyl-tRNA synthetase (EPRS), thereby activating the amino acid response (AAR). We now show that HF treatment selectively inhibits inflammatory responses in diverse cell types and that these therapeutic benefits occur in cells that lack GCN2, the signature effector of the AAR. Depletion of arginine, histidine, or lysine from cultured fibroblast-like synoviocytes recapitulates key aspects of HF treatment, without utilizing GCN2 or mammalian target of rapamycin complex 1 pathway signaling. Like HF, the threonyl-tRNA synthetase inhibitor borrelidin suppresses the induction of tissue remodeling and inflammatory mediators in cytokine-stimulated fibroblast-like synoviocytes without GCN2, but both aminoacyl-tRNA synthetase (aaRS) inhibitors are sensitive to the removal of GCN1. GCN1, an upstream component of the AAR pathway, binds to ribosomes and is required for GCN2 activation. These observations indicate that aaRS inhibitors, like HF, can modulate inflammatory response without the AAR/GCN2 signaling cassette, and that GCN1 has a role that is distinct from its activation of GCN2. We propose that GCN1 participates in a previously unrecognized amino acid sensor pathway that branches from the canonical AAR.</div>
</front>
</TEI>
<pubmed>
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<DateCompleted>
<Year>2020</Year>
<Month>07</Month>
<Day>27</Day>
</DateCompleted>
<DateRevised>
<Year>2020</Year>
<Month>10</Month>
<Day>06</Day>
</DateRevised>
<Article PubModel="Print-Electronic">
<Journal>
<ISSN IssnType="Electronic">1091-6490</ISSN>
<JournalIssue CitedMedium="Internet">
<Volume>117</Volume>
<Issue>16</Issue>
<PubDate>
<Year>2020</Year>
<Month>04</Month>
<Day>21</Day>
</PubDate>
</JournalIssue>
<Title>Proceedings of the National Academy of Sciences of the United States of America</Title>
<ISOAbbreviation>Proc Natl Acad Sci U S A</ISOAbbreviation>
</Journal>
<ArticleTitle>Aminoacyl-tRNA synthetase inhibition activates a pathway that branches from the canonical amino acid response in mammalian cells.</ArticleTitle>
<Pagination>
<MedlinePgn>8900-8911</MedlinePgn>
</Pagination>
<ELocationID EIdType="doi" ValidYN="Y">10.1073/pnas.1913788117</ELocationID>
<Abstract>
<AbstractText>Signaling pathways that sense amino acid abundance are integral to tissue homeostasis and cellular defense. Our laboratory has previously shown that halofuginone (HF) inhibits the prolyl-tRNA synthetase catalytic activity of glutamyl-prolyl-tRNA synthetase (EPRS), thereby activating the amino acid response (AAR). We now show that HF treatment selectively inhibits inflammatory responses in diverse cell types and that these therapeutic benefits occur in cells that lack GCN2, the signature effector of the AAR. Depletion of arginine, histidine, or lysine from cultured fibroblast-like synoviocytes recapitulates key aspects of HF treatment, without utilizing GCN2 or mammalian target of rapamycin complex 1 pathway signaling. Like HF, the threonyl-tRNA synthetase inhibitor borrelidin suppresses the induction of tissue remodeling and inflammatory mediators in cytokine-stimulated fibroblast-like synoviocytes without GCN2, but both aminoacyl-tRNA synthetase (aaRS) inhibitors are sensitive to the removal of GCN1. GCN1, an upstream component of the AAR pathway, binds to ribosomes and is required for GCN2 activation. These observations indicate that aaRS inhibitors, like HF, can modulate inflammatory response without the AAR/GCN2 signaling cassette, and that GCN1 has a role that is distinct from its activation of GCN2. We propose that GCN1 participates in a previously unrecognized amino acid sensor pathway that branches from the canonical AAR.</AbstractText>
</Abstract>
<AuthorList CompleteYN="Y">
<Author ValidYN="Y">
<LastName>Kim</LastName>
<ForeName>Yeonjin</ForeName>
<Initials>Y</Initials>
<AffiliationInfo>
<Affiliation>Department of Developmental Biology, Harvard School of Dental Medicine, Boston, MA 02115.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y">
<LastName>Sundrud</LastName>
<ForeName>Mark S</ForeName>
<Initials>MS</Initials>
<Identifier Source="ORCID">0000-0002-4249-0525</Identifier>
<AffiliationInfo>
<Affiliation>Department of Immunology and Microbiology, The Scripps Research Institute, Jupiter, FL 33458.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y">
<LastName>Zhou</LastName>
<ForeName>Changqian</ForeName>
<Initials>C</Initials>
<AffiliationInfo>
<Affiliation>Department of Developmental Biology, Harvard School of Dental Medicine, Boston, MA 02115.</Affiliation>
</AffiliationInfo>
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<LastName>Edenius</LastName>
<ForeName>Maja</ForeName>
<Initials>M</Initials>
<AffiliationInfo>
<Affiliation>Department of Developmental Biology, Harvard School of Dental Medicine, Boston, MA 02115.</Affiliation>
</AffiliationInfo>
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<LastName>Zocco</LastName>
<ForeName>Davide</ForeName>
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<Affiliation>Department of Developmental Biology, Harvard School of Dental Medicine, Boston, MA 02115.</Affiliation>
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<ForeName>Kristen</ForeName>
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<AffiliationInfo>
<Affiliation>Department of Developmental Biology, Harvard School of Dental Medicine, Boston, MA 02115.</Affiliation>
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<LastName>Zhang</LastName>
<ForeName>Miao</ForeName>
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<AffiliationInfo>
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</AffiliationInfo>
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<ForeName>Ralph</ForeName>
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<AffiliationInfo>
<Affiliation>Center for Systems Biology, Massachusetts General Hospital, Boston, MA 02114.</Affiliation>
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<ForeName>Anjana</ForeName>
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<Affiliation>Division of Signaling and Gene Expression, La Jolla Institute for Immunology, La Jolla, CA 92037.</Affiliation>
</AffiliationInfo>
</Author>
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<LastName>Yeo</LastName>
<ForeName>Chang-Yeol</ForeName>
<Initials>CY</Initials>
<AffiliationInfo>
<Affiliation>Department of Life Science, Division of Life and Pharmaceutical Sciences, Ewha Womans University, 03760 Seoul, Korea.</Affiliation>
</AffiliationInfo>
</Author>
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<LastName>Noss</LastName>
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<Affiliation>Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115.</Affiliation>
</AffiliationInfo>
<AffiliationInfo>
<Affiliation>Division of Rheumatology, Department of Medicine, University of Washington, Seattle, WA 98195.</Affiliation>
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<LastName>Brenner</LastName>
<ForeName>Michael B</ForeName>
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<ForeName>Malcolm</ForeName>
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<Affiliation>Department of Developmental Biology, Harvard School of Dental Medicine, Boston, MA 02115; mbrenner@research.bwh.harvard.edu mwhitman@hms.harvard.edu tkeller@hms.harvard.edu.</Affiliation>
</AffiliationInfo>
</Author>
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<LastName>Keller</LastName>
<ForeName>Tracy L</ForeName>
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<AffiliationInfo>
<Affiliation>Department of Developmental Biology, Harvard School of Dental Medicine, Boston, MA 02115; mbrenner@research.bwh.harvard.edu mwhitman@hms.harvard.edu tkeller@hms.harvard.edu.</Affiliation>
</AffiliationInfo>
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<Acronym>AI</Acronym>
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<Country>United States</Country>
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<Chemical>
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<Chemical>
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<QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName>
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<MeshHeading>
<DescriptorName UI="D000604" MajorTopicYN="N">Amino Acyl-tRNA Synthetases</DescriptorName>
<QualifierName UI="Q000037" MajorTopicYN="Y">antagonists & inhibitors</QualifierName>
<QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName>
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<MeshHeading>
<DescriptorName UI="D000818" MajorTopicYN="N">Animals</DescriptorName>
</MeshHeading>
<MeshHeading>
<DescriptorName UI="D000893" MajorTopicYN="N">Anti-Inflammatory Agents</DescriptorName>
<QualifierName UI="Q000494" MajorTopicYN="Y">pharmacology</QualifierName>
<QualifierName UI="Q000627" MajorTopicYN="N">therapeutic use</QualifierName>
</MeshHeading>
<MeshHeading>
<DescriptorName UI="D001172" MajorTopicYN="N">Arthritis, Rheumatoid</DescriptorName>
<QualifierName UI="Q000188" MajorTopicYN="Y">drug therapy</QualifierName>
<QualifierName UI="Q000276" MajorTopicYN="N">immunology</QualifierName>
<QualifierName UI="Q000473" MajorTopicYN="N">pathology</QualifierName>
<QualifierName UI="Q000601" MajorTopicYN="N">surgery</QualifierName>
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<MeshHeading>
<DescriptorName UI="D002460" MajorTopicYN="N">Cell Line</DescriptorName>
</MeshHeading>
<MeshHeading>
<DescriptorName UI="D005347" MajorTopicYN="N">Fibroblasts</DescriptorName>
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<MeshHeading>
<DescriptorName UI="D055785" MajorTopicYN="N">Gene Knockdown Techniques</DescriptorName>
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<MeshHeading>
<DescriptorName UI="D061307" MajorTopicYN="N">Human Umbilical Vein Endothelial Cells</DescriptorName>
</MeshHeading>
<MeshHeading>
<DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName>
</MeshHeading>
<MeshHeading>
<DescriptorName UI="D008168" MajorTopicYN="N">Lung</DescriptorName>
<QualifierName UI="Q000166" MajorTopicYN="N">cytology</QualifierName>
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<MeshHeading>
<DescriptorName UI="D000076222" MajorTopicYN="N">Mechanistic Target of Rapamycin Complex 1</DescriptorName>
<QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName>
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<MeshHeading>
<DescriptorName UI="D051379" MajorTopicYN="N">Mice</DescriptorName>
</MeshHeading>
<MeshHeading>
<DescriptorName UI="D018345" MajorTopicYN="N">Mice, Knockout</DescriptorName>
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<QualifierName UI="Q000494" MajorTopicYN="Y">pharmacology</QualifierName>
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<DescriptorName UI="D061251" MajorTopicYN="N">Primary Cell Culture</DescriptorName>
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<DescriptorName UI="D017346" MajorTopicYN="N">Protein-Serine-Threonine Kinases</DescriptorName>
<QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName>
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<DescriptorName UI="D016601" MajorTopicYN="N">RNA-Binding Proteins</DescriptorName>
<QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName>
<QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName>
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<DescriptorName UI="D000081246" MajorTopicYN="N">RNA-Seq</DescriptorName>
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<DescriptorName UI="D015398" MajorTopicYN="N">Signal Transduction</DescriptorName>
<QualifierName UI="Q000187" MajorTopicYN="Y">drug effects</QualifierName>
<QualifierName UI="Q000276" MajorTopicYN="N">immunology</QualifierName>
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<MeshHeading>
<DescriptorName UI="D013583" MajorTopicYN="N">Synovial Membrane</DescriptorName>
<QualifierName UI="Q000166" MajorTopicYN="N">cytology</QualifierName>
<QualifierName UI="Q000473" MajorTopicYN="N">pathology</QualifierName>
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<DescriptorName UI="D000070918" MajorTopicYN="N">Synoviocytes</DescriptorName>
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<MeshHeading>
<DescriptorName UI="D015534" MajorTopicYN="N">Trans-Activators</DescriptorName>
<QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName>
<QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName>
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<Keyword MajorTopicYN="Y">GCN1</Keyword>
<Keyword MajorTopicYN="Y">GCN2</Keyword>
<Keyword MajorTopicYN="Y">amino acid catabolism</Keyword>
<Keyword MajorTopicYN="Y">aminoacyl-tRNA synthetase (aaRS) inhibition</Keyword>
<Keyword MajorTopicYN="Y">halofuginone (HF)</Keyword>
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<CoiStatement>The authors declare no competing interest.</CoiStatement>
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