title: Translation control of TAK1 mRNA by hnRNP K modulates LPS-induced macrophage activation.
abstract: Macrophage activation by bacterial lipopolysaccharides (LPS) is induced through Toll-like receptor 4 (TLR4). The synthesis and activity of TLR4 downstream signaling molecules modulates the expression of pro- and anti-inflammatory cytokines. To address the impact of post-transcriptional regulation on that process, we performed RIP-Chip analysis. Differential association of mRNAs with heterogeneous nuclear ribonucleoprotein K (hnRNP K), an mRNA-specific translational regulator in differentiating hematopoietic cells, was studied in noninduced and LPS-activated macrophages. Analysis of interactions affected by LPS revealed several mRNAs encoding TLR4 downstream kinases and their modulators. We focused on transforming growth factor-β-activated kinase 1 (TAK1) a central player in TLR4 signaling. HnRNP K interacts specifically with a sequence in the TAK1 mRNA 3' UTR in vitro. Silencing of hnRNP K does not affect TAK1 mRNA synthesis or stability but enhances TAK1 mRNA translation, resulting in elevated TNF-α, IL-1β, and IL-10 mRNA expression. Our data suggest that the hnRNP K-3' UTR complex inhibits TAK1 mRNA translation in noninduced macrophages. LPS-dependent TLR4 activation abrogates translational repression and newly synthesized TAK1 boosts macrophage inflammatory response.
authors.affiliation: Department of Intensive Care and Intermediate Care, University Hospital, RWTH Aachen University, 52074 Aachen, Germany.
authors.forename: Anke
authors.initials: A
authors.lastname: Liepelt
authors.affiliation: Department of Intensive Care and Intermediate Care, University Hospital, RWTH Aachen University, 52074 Aachen, Germany.
authors.forename: Jana C
authors.initials: JC
authors.lastname: Mossanen
authors.affiliation: Chip Facility, IZKF Aachen, University Hospital, RWTH Aachen University, 52074 Aachen, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Denecke
authors.affiliation: Department of Internal Medicine III, University Hospital, RWTH Aachen University, 52074 Aachen, Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Heymann
authors.affiliation: Department of Intensive Care and Intermediate Care, University Hospital, RWTH Aachen University, 52074 Aachen, Germany.
authors.forename: Rebecca
authors.initials: R
authors.lastname: De Santis
authors.affiliation: Department of Internal Medicine III, University Hospital, RWTH Aachen University, 52074 Aachen, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Tacke
authors.affiliation: Department of Intensive Care and Intermediate Care, University Hospital, RWTH Aachen University, 52074 Aachen, Germany.
authors.forename: Gernot
authors.initials: G
authors.lastname: Marx
authors.affiliation: Department of Intensive Care and Intermediate Care, University Hospital, RWTH Aachen University, 52074 Aachen, Germany.
authors.forename: Dirk H
authors.initials: DH
authors.lastname: Ostareck
authors.affiliation: Department of Intensive Care and Intermediate Care, University Hospital, RWTH Aachen University, 52074 Aachen, Germany.
authors.forename: Antje
authors.initials: A
authors.lastname: Ostareck-Lederer
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics / Q000276:immunology; D000818:Animals; D002460:Cell Line; D005786:Gene Expression Regulation / Q000235:genetics / Q000276:immunology; D034641:Heterogeneous-Nuclear Ribonucleoprotein K / Q000235:genetics* / Q000276:immunology; D007249:Inflammation / Q000235:genetics / Q000276:immunology; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology; D053583:Interleukin-1beta / Q000235:genetics / Q000276:immunology; D008070:Lipopolysaccharides / Q000276:immunology*; D020930:MAP Kinase Kinase Kinases / Q000235:genetics* / Q000276:immunology; D008262:Macrophage Activation / Q000235:genetics / Q000276:immunology*; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D014176:Protein Biosynthesis / Q000235:genetics* / Q000276:immunology; D012323:RNA Processing, Post-Transcriptional / Q000235:genetics / Q000276:immunology; D012333:RNA, Messenger / Q000235:genetics* / Q000276:immunology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D020413:3' Untranslated Regions; D034641:Heterogeneous-Nuclear Ribonucleoprotein K; D016753:Interleukin-10; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D020930:MAP Kinase Kinase Kinases; D012333:RNA, Messenger; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D000099151:MAP Kinase Kinase Kinase 7; C556062:IL10 protein, mouse; C493487:Tlr4 protein, mouse
keywords: LPS; TAK1 mRNA; TLR4-signaling; hnRNP K; post-transcriptional regulation
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