Inhibition of the inflammatory response to stress by targeting interaction between PKR and its cellular activator PACT
PKR is a cellular kinase involved in the regulation of the integrative stress response (ISR) and pro-inflammatory pathways. Two N-terminal dsRNA Binding Domains (DRBD) are required for activation of PKR, by interaction with either dsRNA or PACT, another cellular DRBD-containing protein. A role for P...
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| Veröffentlicht in: | Scientific reports 2017-11, Vol.7 (1), p.16129-15, Article 16129 |
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| creator | Dabo, Stephanie Maillard, Patrick Collados Rodriguez, Milagros Hansen, Marianne Doré Mazouz, Sabrina Bigot, Donna-Joe Tible, Marion Janvier, Geneviève Helynck, Olivier Cassonnet, Patricia Jacob, Yves Bellalou, Jacques Gatignol, Anne Patel, Rekha C. Hugon, Jacques Munier-Lehmann, Hélène Meurs, Eliane F. |
| description | PKR is a cellular kinase involved in the regulation of the integrative stress response (ISR) and pro-inflammatory pathways. Two N-terminal dsRNA Binding Domains (DRBD) are required for activation of PKR, by interaction with either dsRNA or PACT, another cellular DRBD-containing protein. A role for PKR and PACT in inflammatory processes linked to neurodegenerative diseases has been proposed and raised interest for pharmacological PKR inhibitors. However, the role of PKR in inflammation is subject to controversy. We identified the flavonoid luteolin as an inhibitor of the PKR/PACT interaction at the level of their DRBDs using high-throughput screening of chemical libraries by homogeneous time-resolved fluorescence. This was further validated using NanoLuc-Based Protein Complementation Assay. Luteolin inhibits PKR phosphorylation, the ISR and the induction of pro-inflammatory cytokines in human THP1 macrophages submitted to oxidative stress and toll-like receptor (TLR) agonist. Similarly, luteolin inhibits induction of pro-inflammatory cytokines in murine microglial macrophages. In contrast, luteolin increased activation of the inflammasome, in a PKR-independent manner. Collectively, these data delineate the importance of PKR in the inflammation process to the ISR and induction of pro-inflammatory cytokines. Pharmacological inhibitors of PKR should be used in combination with drugs targeting directly the inflammasome. |
| doi_str_mv | 10.1038/s41598-017-16089-8 |
| format | Article |
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Two N-terminal dsRNA Binding Domains (DRBD) are required for activation of PKR, by interaction with either dsRNA or PACT, another cellular DRBD-containing protein. A role for PKR and PACT in inflammatory processes linked to neurodegenerative diseases has been proposed and raised interest for pharmacological PKR inhibitors. However, the role of PKR in inflammation is subject to controversy. We identified the flavonoid luteolin as an inhibitor of the PKR/PACT interaction at the level of their DRBDs using high-throughput screening of chemical libraries by homogeneous time-resolved fluorescence. This was further validated using NanoLuc-Based Protein Complementation Assay. Luteolin inhibits PKR phosphorylation, the ISR and the induction of pro-inflammatory cytokines in human THP1 macrophages submitted to oxidative stress and toll-like receptor (TLR) agonist. Similarly, luteolin inhibits induction of pro-inflammatory cytokines in murine microglial macrophages. In contrast, luteolin increased activation of the inflammasome, in a PKR-independent manner. Collectively, these data delineate the importance of PKR in the inflammation process to the ISR and induction of pro-inflammatory cytokines. Pharmacological inhibitors of PKR should be used in combination with drugs targeting directly the inflammasome.</description><identifier>ISSN: 2045-2322</identifier><identifier>EISSN: 2045-2322</identifier><identifier>DOI: 10.1038/s41598-017-16089-8</identifier><identifier>PMID: 29170442</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>38 ; 38/1 ; 631/80 ; 692/420 ; Cell activation ; Cellular Biology ; Cytokines ; Double-stranded RNA ; Drug delivery ; High-throughput screening ; Humanities and Social Sciences ; Inflammasomes ; Inflammation ; Life Sciences ; Macrophages ; Microbiology and Parasitology ; multidisciplinary ; Neurodegenerative diseases ; Oxidative stress ; Phosphorylation ; Science ; Science (multidisciplinary) ; Subcellular Processes ; Toll-like receptors ; Virology</subject><ispartof>Scientific reports, 2017-11, Vol.7 (1), p.16129-15, Article 16129</ispartof><rights>The Author(s) 2017</rights><rights>2017. 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Two N-terminal dsRNA Binding Domains (DRBD) are required for activation of PKR, by interaction with either dsRNA or PACT, another cellular DRBD-containing protein. A role for PKR and PACT in inflammatory processes linked to neurodegenerative diseases has been proposed and raised interest for pharmacological PKR inhibitors. However, the role of PKR in inflammation is subject to controversy. We identified the flavonoid luteolin as an inhibitor of the PKR/PACT interaction at the level of their DRBDs using high-throughput screening of chemical libraries by homogeneous time-resolved fluorescence. This was further validated using NanoLuc-Based Protein Complementation Assay. Luteolin inhibits PKR phosphorylation, the ISR and the induction of pro-inflammatory cytokines in human THP1 macrophages submitted to oxidative stress and toll-like receptor (TLR) agonist. Similarly, luteolin inhibits induction of pro-inflammatory cytokines in murine microglial macrophages. In contrast, luteolin increased activation of the inflammasome, in a PKR-independent manner. Collectively, these data delineate the importance of PKR in the inflammation process to the ISR and induction of pro-inflammatory cytokines. Pharmacological inhibitors of PKR should be used in combination with drugs targeting directly the inflammasome.</description><subject>38</subject><subject>38/1</subject><subject>631/80</subject><subject>692/420</subject><subject>Cell activation</subject><subject>Cellular Biology</subject><subject>Cytokines</subject><subject>Double-stranded RNA</subject><subject>Drug delivery</subject><subject>High-throughput screening</subject><subject>Humanities and Social Sciences</subject><subject>Inflammasomes</subject><subject>Inflammation</subject><subject>Life Sciences</subject><subject>Macrophages</subject><subject>Microbiology and Parasitology</subject><subject>multidisciplinary</subject><subject>Neurodegenerative diseases</subject><subject>Oxidative stress</subject><subject>Phosphorylation</subject><subject>Science</subject><subject>Science (multidisciplinary)</subject><subject>Subcellular Processes</subject><subject>Toll-like 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Stephanie</au><au>Maillard, Patrick</au><au>Collados Rodriguez, Milagros</au><au>Hansen, Marianne Doré</au><au>Mazouz, Sabrina</au><au>Bigot, Donna-Joe</au><au>Tible, Marion</au><au>Janvier, Geneviève</au><au>Helynck, Olivier</au><au>Cassonnet, Patricia</au><au>Jacob, Yves</au><au>Bellalou, Jacques</au><au>Gatignol, Anne</au><au>Patel, Rekha C.</au><au>Hugon, Jacques</au><au>Munier-Lehmann, Hélène</au><au>Meurs, Eliane F.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Inhibition of the inflammatory response to stress by targeting interaction between PKR and its cellular activator PACT</atitle><jtitle>Scientific reports</jtitle><stitle>Sci Rep</stitle><addtitle>Sci Rep</addtitle><date>2017-11-23</date><risdate>2017</risdate><volume>7</volume><issue>1</issue><spage>16129</spage><epage>15</epage><pages>16129-15</pages><artnum>16129</artnum><issn>2045-2322</issn><eissn>2045-2322</eissn><abstract>PKR is a cellular kinase involved in the regulation of the integrative stress response (ISR) and pro-inflammatory pathways. Two N-terminal dsRNA Binding Domains (DRBD) are required for activation of PKR, by interaction with either dsRNA or PACT, another cellular DRBD-containing protein. A role for PKR and PACT in inflammatory processes linked to neurodegenerative diseases has been proposed and raised interest for pharmacological PKR inhibitors. However, the role of PKR in inflammation is subject to controversy. We identified the flavonoid luteolin as an inhibitor of the PKR/PACT interaction at the level of their DRBDs using high-throughput screening of chemical libraries by homogeneous time-resolved fluorescence. This was further validated using NanoLuc-Based Protein Complementation Assay. Luteolin inhibits PKR phosphorylation, the ISR and the induction of pro-inflammatory cytokines in human THP1 macrophages submitted to oxidative stress and toll-like receptor (TLR) agonist. Similarly, luteolin inhibits induction of pro-inflammatory cytokines in murine microglial macrophages. In contrast, luteolin increased activation of the inflammasome, in a PKR-independent manner. Collectively, these data delineate the importance of PKR in the inflammation process to the ISR and induction of pro-inflammatory cytokines. Pharmacological inhibitors of PKR should be used in combination with drugs targeting directly the inflammasome.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>29170442</pmid><doi>10.1038/s41598-017-16089-8</doi><tpages>15</tpages><orcidid>https://orcid.org/0000-0001-9125-2374</orcidid><orcidid>https://orcid.org/0000-0003-0411-7153</orcidid><orcidid>https://orcid.org/0000-0002-6275-0128</orcidid><orcidid>https://orcid.org/0000-0001-7579-8561</orcidid><orcidid>https://orcid.org/0000-0001-5634-0408</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | 38 38/1 631/80 692/420 Cell activation Cellular Biology Cytokines Double-stranded RNA Drug delivery High-throughput screening Humanities and Social Sciences Inflammasomes Inflammation Life Sciences Macrophages Microbiology and Parasitology multidisciplinary Neurodegenerative diseases Oxidative stress Phosphorylation Science Science (multidisciplinary) Subcellular Processes Toll-like receptors Virology |
| title | Inhibition of the inflammatory response to stress by targeting interaction between PKR and its cellular activator PACT |
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