title: Polyubiquitination of Transforming Growth Factor β-activated Kinase 1 (TAK1) at Lysine 562 Residue Regulates TLR4-mediated JNK and p38 MAPK Activation.
abstract: Toll-like receptor 4 (TLR4) plays an important role in innate immunity by eliciting inflammation. Upon receptor engagement, transforming growth factor β-activated kinase 1 (TAK1) is an essential mediator that transmits a signal from the receptor to downstream effectors, IκB kinase (IKK) and the mitogen-activated protein kinases (MAPKs), which control the production of inflammatory cytokines. However, the association between phosphorylation and ubiquitination of TAK1 is not yet clear. Here, we examined the crosstalk between phosphorylation and polyubiquitination of TAK1 and further investigated the mechanism of distinct activation of MAPKs and IKK. Inhibition of TAK1 phosphorylation enhanced Lys63-linked polyubiquitination of TAK1. Conversely, ubiquitin modification was counteracted by phospho-mimic TAK1 mutant, T(184,187)D. Moreover, using LC-MS analysis, Lys562 of TAK1 was identified as a novel Lys63-linked ubiquitination site and as the key residue in the feedback regulation. Mutation of Lys562 of TAK1 leads to a decrease in TAK1 phosphorylation and specific inhibition of the MAPK pathway, but has no effect on formation of the TAK1-containing complex. Our findings demonstrate a feedback loop for phosphorylation and ubiquitination of TAK1, indicating a dynamic regulation between TAK1 polyubiquitiantion and phosphorylated activation, and the molecular mechanism by which IKK and MAPKs are differentially activated in the TLR4 pathway.
authors.affiliation: Institute of Biochemistry and Molecular Biology, School of Life Sciences, National Yang-Ming University, Taipei 11221, Taiwan (ROC).
authors.forename: I-Ting
authors.initials: IT
authors.lastname: Chen
authors.affiliation: 1] Institute of Biochemistry and Molecular Biology, School of Life Sciences, National Yang-Ming University, Taipei 11221, Taiwan (ROC) [2] Institute of Bioscience and Biotechnology, College of Life Sciences, National Taiwan Ocean University, Keelung20224, Taiwan (ROC).
authors.forename: Pang-Hung
authors.initials: PH
authors.lastname: Hsu
authors.affiliation: Institute of Biochemistry and Molecular Biology, School of Life Sciences, National Yang-Ming University, Taipei 11221, Taiwan (ROC).
authors.forename: Wan-Ching
authors.initials: WC
authors.lastname: Hsu
authors.affiliation: 1] Institute of Microbiology and Immunology, School of Life Sciences, National Yang-Ming University, Taipei 11221, Taiwan (ROC) [2] Infection and Immunity Research Center, National Yang-Ming University, Taipei 11221, Taiwan (ROC).
authors.forename: Nien-Jung
authors.initials: NJ
authors.lastname: Chen
authors.affiliation: 1] Institute of Biochemistry and Molecular Biology, School of Life Sciences, National Yang-Ming University, Taipei 11221, Taiwan (ROC) [2] Infection and Immunity Research Center, National Yang-Ming University, Taipei 11221, Taiwan (ROC).
authors.forename: Ping-Hui
authors.initials: PH
authors.lastname: Tseng
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D016207:Cytokines / Q000096:biosynthesis; D004789:Enzyme Activation; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008239:Lysine / Q000378:metabolism*; D020930:MAP Kinase Kinase Kinases / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D010766:Phosphorylation; D011485:Protein Binding; D016415:Sequence Alignment; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D054875:Ubiquitination; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D016207:Cytokines; D051550:I-kappa B Kinase; D048031:JNK Mitogen-Activated Protein Kinases; D008239:Lysine; D020930:MAP Kinase Kinase Kinases; D048029:TNF Receptor-Associated Factor 6; D051197:Toll-Like Receptor 4; D016212:Transforming Growth Factor beta; D048051:p38 Mitogen-Activated Protein Kinases; D000099151:MAP Kinase Kinase Kinase 7; C486300:TAB1 protein, human