Phosphorylation of TRIM28 Enhances the Expression of IFN-β and Proinflammatory Cytokines During HPAIV Infection of Human Lung Epithelial Cells.
Identifieur interne : 000974 ( Main/Exploration ); précédent : 000973; suivant : 000975Phosphorylation of TRIM28 Enhances the Expression of IFN-β and Proinflammatory Cytokines During HPAIV Infection of Human Lung Epithelial Cells.
Auteurs : Tim Krischuns [Allemagne] ; Franziska Günl [Allemagne] ; Lea Henschel [Allemagne] ; Marco Binder [Allemagne] ; Joschka Willemsen [Allemagne] ; Sebastian Schloer [Allemagne] ; Ursula Rescher [Allemagne] ; Vanessa Gerlt [Allemagne] ; Gert Zimmer [Suisse] ; Carolin Nordhoff [Allemagne] ; Stephan Ludwig [Allemagne] ; Linda Brunotte [Allemagne]Source :
- Frontiers in immunology [ 1664-3224 ] ; 2018.
Descripteurs français
- KwdFr :
- Analyse de variance, Animaux, Cellules A549, Cellules HEK293, Cellules endothéliales de la veine ombilicale humaine, Cellules épithéliales (virologie), Grippe humaine (métabolisme), Humains, Interféron bêta (métabolisme), Phosphorylation, Poumon (virologie), Protéine-58 à domaine DEAD (métabolisme), Ribosomal Protein S6 Kinases, 90-kDa (métabolisme), Systèmes CRISPR-Cas (génétique), Techniques de knock-down de gènes, Techniques de transfert de gènes, Virus de la grippe A (métabolisme), p38 Mitogen-Activated Protein Kinases (métabolisme).
- MESH :
- génétique : Systèmes CRISPR-Cas.
- métabolisme : Grippe humaine, Interféron bêta, Protéine-58 à domaine DEAD, Ribosomal Protein S6 Kinases, 90-kDa, Virus de la grippe A, p38 Mitogen-Activated Protein Kinases.
- virologie : Cellules épithéliales, Poumon.
- Analyse de variance, Animaux, Cellules A549, Cellules HEK293, Cellules endothéliales de la veine ombilicale humaine, Humains, Phosphorylation, Techniques de knock-down de gènes, Techniques de transfert de gènes.
English descriptors
- KwdEn :
- A549 Cells, Analysis of Variance, Animals, CRISPR-Cas Systems (genetics), Chlorocebus aethiops, DEAD Box Protein 58 (metabolism), Epithelial Cells (virology), Gene Knockdown Techniques, Gene Transfer Techniques, HEK293 Cells, Human Umbilical Vein Endothelial Cells, Humans, Influenza A virus (metabolism), Influenza, Human (metabolism), Interferon-beta (metabolism), Lung (virology), Phosphorylation, Ribosomal Protein S6 Kinases, 90-kDa (metabolism), Tripartite Motif-Containing Protein 28 (genetics), Tripartite Motif-Containing Protein 28 (metabolism), p38 Mitogen-Activated Protein Kinases (metabolism).
- MESH :
- chemical , genetics : Tripartite Motif-Containing Protein 28.
- chemical , metabolism : DEAD Box Protein 58, Interferon-beta, Ribosomal Protein S6 Kinases, 90-kDa, Tripartite Motif-Containing Protein 28, p38 Mitogen-Activated Protein Kinases.
- genetics : CRISPR-Cas Systems.
- metabolism : Influenza A virus, Influenza, Human.
- virology : Epithelial Cells, Lung.
- A549 Cells, Analysis of Variance, Animals, Chlorocebus aethiops, Gene Knockdown Techniques, Gene Transfer Techniques, HEK293 Cells, Human Umbilical Vein Endothelial Cells, Humans, Phosphorylation.
Abstract
Human infection with highly pathogenic avian influenza viruses (HPAIV) is often associated with severe tissue damage due to hyperinduction of interferons and proinflammatory cytokines. The reasons for this excessive cytokine expression are still incompletely understood, which has hampered the development of efficient immunomodulatory treatment options. The host protein TRIM28 associates to the promoter regions of over 13,000 genes and is recognized as a genomic corepressor and negative immune regulator. TRIM28 corepressor activity is regulated by post-translational modifications, specifically phosphorylation of S473, which modulates binding of TRIM28 to the heterochromatin-binding protein HP1. Here, we identified TRIM28 as a key immune regulator leading to increased IFN-β and proinflammatory cytokine levels during infection with HPAIV. Using influenza A virus strains of the subtype H1N1 as well as HPAIV of subtypes H7N7, H7N9, and H5N1, we could demonstrate that strain-specific phosphorylation of TRIM28 S473 is induced by a signaling cascade constituted of PKR, p38 MAPK, and MSK1 in response to RIG-I independent sensing of viral RNA. Furthermore, using chemical inhibitors as well as knockout cell lines, our results suggest that phosphorylation of S473 facilitates a functional switch leading to increased levels of IFN-β, IL-6, and IL-8. In summary, we have identified TRIM28 as a critical factor controlling excessive expression of type I IFNs as well as proinflammatory cytokines during infection with H5N1, H7N7, and H7N9 HPAIV. In addition, our data indicate a novel mechanism of PKR-mediated IFN-β expression, which could lay the ground for novel treatment options aiming at rebalancing dysregulated immune responses during severe HPAIV infection.
DOI: 10.3389/fimmu.2018.02229
PubMed: 30323812
Affiliations:
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Franziska" sort="Gunl, Franziska" uniqKey="Gunl F" first="Franziska" last="Günl">Franziska Günl</name><affiliation wicri:level="1"><nlm:affiliation>Institute of Virology Muenster, Westfaelische Wilhelms-University Muenster, Muenster, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Virology Muenster, Westfaelische Wilhelms-University Muenster, Muenster</wicri:regionArea><wicri:noRegion>Muenster</wicri:noRegion><wicri:noRegion>Muenster</wicri:noRegion><wicri:noRegion>Muenster</wicri:noRegion></affiliation></author><author><name sortKey="Henschel, Lea" sort="Henschel, Lea" uniqKey="Henschel L" first="Lea" last="Henschel">Lea Henschel</name><affiliation wicri:level="1"><nlm:affiliation>Institute of Virology Muenster, Westfaelische Wilhelms-University Muenster, Muenster, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Virology Muenster, Westfaelische Wilhelms-University Muenster, Muenster</wicri:regionArea><wicri:noRegion>Muenster</wicri:noRegion><wicri:noRegion>Muenster</wicri:noRegion><wicri:noRegion>Muenster</wicri:noRegion></affiliation></author><author><name sortKey="Binder, Marco" sort="Binder, Marco" uniqKey="Binder M" first="Marco" last="Binder">Marco Binder</name><affiliation wicri:level="3"><nlm:affiliation>Research Group "Dynamics of Early Viral Infection and the Innate Antiviral Response", Division Virus-Associated Carcinogenesis (F170), German Cancer Research Center (DKFZ), Heidelberg, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Research Group "Dynamics of Early Viral Infection and the Innate Antiviral Response", Division Virus-Associated Carcinogenesis (F170), German Cancer Research Center (DKFZ), Heidelberg</wicri:regionArea><placeName><region type="land" nuts="1">Bade-Wurtemberg</region><region type="district" nuts="2">District de Karlsruhe</region><settlement type="city">Heidelberg</settlement></placeName></affiliation></author><author><name sortKey="Willemsen, Joschka" sort="Willemsen, Joschka" uniqKey="Willemsen J" first="Joschka" last="Willemsen">Joschka Willemsen</name><affiliation wicri:level="3"><nlm:affiliation>Research Group "Dynamics of Early Viral Infection and the Innate Antiviral Response", Division Virus-Associated Carcinogenesis (F170), German Cancer Research Center (DKFZ), Heidelberg, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Research Group "Dynamics of Early Viral Infection and the Innate Antiviral Response", Division Virus-Associated Carcinogenesis (F170), German Cancer Research Center (DKFZ), Heidelberg</wicri:regionArea><placeName><region type="land" nuts="1">Bade-Wurtemberg</region><region type="district" nuts="2">District de Karlsruhe</region><settlement type="city">Heidelberg</settlement></placeName></affiliation></author><author><name sortKey="Schloer, Sebastian" sort="Schloer, Sebastian" uniqKey="Schloer S" first="Sebastian" last="Schloer">Sebastian Schloer</name><affiliation wicri:level="1"><nlm:affiliation>Cluster of Excellence "Cells in Motion", Westfaelische Wilhelms-University Muenster, Muenster, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Cluster of Excellence "Cells in Motion", Westfaelische Wilhelms-University Muenster, Muenster</wicri:regionArea><wicri:noRegion>Muenster</wicri:noRegion><wicri:noRegion>Muenster</wicri:noRegion><wicri:noRegion>Muenster</wicri:noRegion></affiliation></author><author><name sortKey="Rescher, Ursula" sort="Rescher, Ursula" uniqKey="Rescher U" first="Ursula" last="Rescher">Ursula Rescher</name><affiliation wicri:level="1"><nlm:affiliation>Cluster of Excellence "Cells in Motion", Westfaelische Wilhelms-University Muenster, Muenster, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Cluster of Excellence "Cells in Motion", Westfaelische Wilhelms-University Muenster, Muenster</wicri:regionArea><wicri:noRegion>Muenster</wicri:noRegion><wicri:noRegion>Muenster</wicri:noRegion><wicri:noRegion>Muenster</wicri:noRegion></affiliation></author><author><name sortKey="Gerlt, Vanessa" sort="Gerlt, Vanessa" uniqKey="Gerlt V" first="Vanessa" last="Gerlt">Vanessa Gerlt</name><affiliation wicri:level="1"><nlm:affiliation>Institute of Virology Muenster, Westfaelische Wilhelms-University Muenster, Muenster, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Virology Muenster, Westfaelische Wilhelms-University Muenster, Muenster</wicri:regionArea><wicri:noRegion>Muenster</wicri:noRegion><wicri:noRegion>Muenster</wicri:noRegion><wicri:noRegion>Muenster</wicri:noRegion></affiliation></author><author><name sortKey="Zimmer, Gert" sort="Zimmer, Gert" uniqKey="Zimmer G" first="Gert" last="Zimmer">Gert Zimmer</name><affiliation wicri:level="3"><nlm:affiliation>Institute of Virology and Immunology (IVI), Bern, Switzerland.</nlm:affiliation><country xml:lang="fr">Suisse</country><wicri:regionArea>Institute of Virology and Immunology (IVI), Bern</wicri:regionArea><placeName><settlement type="city">Berne</settlement><region type="région" nuts="3">Canton de Berne</region></placeName></affiliation></author><author><name sortKey="Nordhoff, Carolin" sort="Nordhoff, Carolin" uniqKey="Nordhoff C" first="Carolin" last="Nordhoff">Carolin Nordhoff</name><affiliation wicri:level="1"><nlm:affiliation>Institute of Virology Muenster, Westfaelische Wilhelms-University Muenster, Muenster, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Virology Muenster, Westfaelische Wilhelms-University Muenster, Muenster</wicri:regionArea><wicri:noRegion>Muenster</wicri:noRegion><wicri:noRegion>Muenster</wicri:noRegion><wicri:noRegion>Muenster</wicri:noRegion></affiliation></author><author><name sortKey="Ludwig, Stephan" sort="Ludwig, Stephan" uniqKey="Ludwig S" first="Stephan" last="Ludwig">Stephan Ludwig</name><affiliation wicri:level="1"><nlm:affiliation>Institute of Virology Muenster, Westfaelische Wilhelms-University Muenster, Muenster, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Virology Muenster, Westfaelische Wilhelms-University Muenster, Muenster</wicri:regionArea><wicri:noRegion>Muenster</wicri:noRegion><wicri:noRegion>Muenster</wicri:noRegion><wicri:noRegion>Muenster</wicri:noRegion></affiliation></author><author><name sortKey="Brunotte, Linda" sort="Brunotte, Linda" uniqKey="Brunotte L" first="Linda" last="Brunotte">Linda Brunotte</name><affiliation wicri:level="1"><nlm:affiliation>Institute of Virology Muenster, Westfaelische Wilhelms-University Muenster, Muenster, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Virology Muenster, Westfaelische Wilhelms-University Muenster, Muenster</wicri:regionArea><wicri:noRegion>Muenster</wicri:noRegion><wicri:noRegion>Muenster</wicri:noRegion><wicri:noRegion>Muenster</wicri:noRegion></affiliation></author></analytic><series><title level="j">Frontiers in immunology</title><idno type="eISSN">1664-3224</idno><imprint><date when="2018" type="published">2018</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>A549 Cells</term><term>Analysis of Variance</term><term>Animals</term><term>CRISPR-Cas Systems (genetics)</term><term>Chlorocebus aethiops</term><term>DEAD Box Protein 58 (metabolism)</term><term>Epithelial Cells (virology)</term><term>Gene Knockdown Techniques</term><term>Gene Transfer Techniques</term><term>HEK293 Cells</term><term>Human Umbilical Vein Endothelial Cells</term><term>Humans</term><term>Influenza A virus (metabolism)</term><term>Influenza, Human (metabolism)</term><term>Interferon-beta (metabolism)</term><term>Lung (virology)</term><term>Phosphorylation</term><term>Ribosomal Protein S6 Kinases, 90-kDa (metabolism)</term><term>Tripartite Motif-Containing Protein 28 (genetics)</term><term>Tripartite Motif-Containing Protein 28 (metabolism)</term><term>p38 Mitogen-Activated Protein Kinases (metabolism)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Analyse de variance</term><term>Animaux</term><term>Cellules A549</term><term>Cellules HEK293</term><term>Cellules endothéliales de la veine ombilicale humaine</term><term>Cellules épithéliales (virologie)</term><term>Grippe humaine (métabolisme)</term><term>Humains</term><term>Interféron bêta (métabolisme)</term><term>Phosphorylation</term><term>Poumon (virologie)</term><term>Protéine-58 à domaine DEAD (métabolisme)</term><term>Ribosomal Protein S6 Kinases, 90-kDa (métabolisme)</term><term>Systèmes CRISPR-Cas (génétique)</term><term>Techniques de knock-down de gènes</term><term>Techniques de transfert de gènes</term><term>Virus de la grippe A (métabolisme)</term><term>p38 Mitogen-Activated Protein Kinases (métabolisme)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Tripartite Motif-Containing Protein 28</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>DEAD Box Protein 58</term><term>Interferon-beta</term><term>Ribosomal Protein S6 Kinases, 90-kDa</term><term>Tripartite Motif-Containing Protein 28</term><term>p38 Mitogen-Activated Protein Kinases</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>CRISPR-Cas Systems</term></keywords><keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Systèmes CRISPR-Cas</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Influenza A virus</term><term>Influenza, Human</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Grippe humaine</term><term>Interféron bêta</term><term>Protéine-58 à domaine DEAD</term><term>Ribosomal Protein S6 Kinases, 90-kDa</term><term>Virus de la grippe A</term><term>p38 Mitogen-Activated Protein Kinases</term></keywords><keywords scheme="MESH" qualifier="virologie" xml:lang="fr"><term>Cellules épithéliales</term><term>Poumon</term></keywords><keywords scheme="MESH" qualifier="virology" xml:lang="en"><term>Epithelial Cells</term><term>Lung</term></keywords><keywords scheme="MESH" xml:lang="en"><term>A549 Cells</term><term>Analysis of Variance</term><term>Animals</term><term>Chlorocebus aethiops</term><term>Gene Knockdown Techniques</term><term>Gene Transfer Techniques</term><term>HEK293 Cells</term><term>Human Umbilical Vein Endothelial Cells</term><term>Humans</term><term>Phosphorylation</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Analyse de variance</term><term>Animaux</term><term>Cellules A549</term><term>Cellules HEK293</term><term>Cellules endothéliales de la veine ombilicale humaine</term><term>Humains</term><term>Phosphorylation</term><term>Techniques de knock-down de gènes</term><term>Techniques de transfert de gènes</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Human infection with highly pathogenic avian influenza viruses (HPAIV) is often associated with severe tissue damage due to hyperinduction of interferons and proinflammatory cytokines. The reasons for this excessive cytokine expression are still incompletely understood, which has hampered the development of efficient immunomodulatory treatment options. The host protein TRIM28 associates to the promoter regions of over 13,000 genes and is recognized as a genomic corepressor and negative immune regulator. TRIM28 corepressor activity is regulated by post-translational modifications, specifically phosphorylation of S473, which modulates binding of TRIM28 to the heterochromatin-binding protein HP1. Here, we identified TRIM28 as a key immune regulator leading to increased IFN-β and proinflammatory cytokine levels during infection with HPAIV. Using influenza A virus strains of the subtype H1N1 as well as HPAIV of subtypes H7N7, H7N9, and H5N1, we could demonstrate that strain-specific phosphorylation of TRIM28 S473 is induced by a signaling cascade constituted of PKR, p38 MAPK, and MSK1 in response to RIG-I independent sensing of viral RNA. Furthermore, using chemical inhibitors as well as knockout cell lines, our results suggest that phosphorylation of S473 facilitates a functional switch leading to increased levels of IFN-β, IL-6, and IL-8. In summary, we have identified TRIM28 as a critical factor controlling excessive expression of type I IFNs as well as proinflammatory cytokines during infection with H5N1, H7N7, and H7N9 HPAIV. In addition, our data indicate a novel mechanism of PKR-mediated IFN-β expression, which could lay the ground for novel treatment options aiming at rebalancing dysregulated immune responses during severe HPAIV infection.</div></front></TEI><affiliations><list><country><li>Allemagne</li><li>Suisse</li></country><region><li>Bade-Wurtemberg</li><li>Canton de Berne</li><li>District de Karlsruhe</li></region><settlement><li>Berne</li><li>Heidelberg</li></settlement></list><tree><country name="Allemagne"><noRegion><name sortKey="Krischuns, Tim" sort="Krischuns, Tim" uniqKey="Krischuns T" first="Tim" last="Krischuns">Tim Krischuns</name></noRegion><name sortKey="Binder, Marco" sort="Binder, Marco" uniqKey="Binder M" first="Marco" last="Binder">Marco Binder</name><name sortKey="Brunotte, Linda" sort="Brunotte, Linda" uniqKey="Brunotte L" first="Linda" last="Brunotte">Linda Brunotte</name><name sortKey="Gerlt, Vanessa" sort="Gerlt, Vanessa" uniqKey="Gerlt V" first="Vanessa" last="Gerlt">Vanessa Gerlt</name><name sortKey="Gunl, Franziska" sort="Gunl, Franziska" uniqKey="Gunl F" first="Franziska" last="Günl">Franziska Günl</name><name sortKey="Henschel, Lea" sort="Henschel, Lea" uniqKey="Henschel L" first="Lea" last="Henschel">Lea Henschel</name><name sortKey="Ludwig, Stephan" sort="Ludwig, Stephan" uniqKey="Ludwig S" first="Stephan" last="Ludwig">Stephan Ludwig</name><name sortKey="Nordhoff, Carolin" sort="Nordhoff, Carolin" uniqKey="Nordhoff C" first="Carolin" last="Nordhoff">Carolin Nordhoff</name><name sortKey="Rescher, Ursula" sort="Rescher, Ursula" uniqKey="Rescher U" first="Ursula" last="Rescher">Ursula Rescher</name><name sortKey="Schloer, Sebastian" sort="Schloer, Sebastian" uniqKey="Schloer S" first="Sebastian" last="Schloer">Sebastian Schloer</name><name sortKey="Willemsen, Joschka" sort="Willemsen, Joschka" uniqKey="Willemsen J" first="Joschka" last="Willemsen">Joschka Willemsen</name></country><country name="Suisse"><region name="Canton de Berne"><name sortKey="Zimmer, Gert" sort="Zimmer, Gert" uniqKey="Zimmer G" first="Gert" last="Zimmer">Gert Zimmer</name></region></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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