title: IRAK-mediated translocation of TRAF6 and TAB2 in the interleukin-1-induced activation of NFkappa B.
abstract: The interleukin-1 (IL-1) receptor-associated kinase (IRAK) is required for the IL-1-induced activation of nuclear factor kappaB and c-Jun N-terminal kinase. The goal of this study was to understand how IRAK activates the intermediate proteins TRAF6, TAK1, TAB1, and TAB2. When IRAK is phosphorylated in response to IL-1, it binds to the membrane where it forms a complex with TRAF6; TRAF6 then dissociates and translocates to the cytosol. The membrane-bound IRAK similarly mediates the IL-1-induced translocation of TAB2 from the membrane to the cytosol. Different regions of IRAK are required for the translocation of TAB2 and TRAF6, suggesting that IRAK mediates the translocation of each protein separately. The translocation of TAB2 and TRAF6 is needed to form a TRAF6-TAK1-TAB1-TAB2 complex in the cytosol and thus activate TAK1. Our results show that IRAK is required for the IL-1-induced phosphorylation of TAK1, TAB1, and TAB2. The phosphorylation of these three proteins correlates strongly with the activation of nuclear factor kappaB but is not necessary to activate c-Jun N-terminal kinase.
authors.affiliation: Department of Immunology, Lerner Research Institute, the Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Qian
authors.forename: M
authors.initials: M
authors.lastname: Commane
authors.forename: J
authors.initials: J
authors.lastname: Ninomiya-Tsuji
authors.forename: K
authors.initials: K
authors.lastname: Matsumoto
authors.forename: X
authors.initials: X
authors.lastname: Li
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D001692:Biological Transport; D002352:Carrier Proteins / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D015699:HIV Envelope Protein gp120 / Q000378:metabolism; D007375:Interleukin-1 / Q000494:pharmacology*; D053592:Interleukin-1 Receptor-Associated Kinases; D016328:NF-kappa B / Q000378:metabolism*; D010766:Phosphorylation; D011494:Protein Kinases / Q000737:chemistry / Q000502:physiology*; D011506:Proteins / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D048029:TNF Receptor-Associated Factor 6; D016212:Transforming Growth Factor beta / Q000494:pharmacology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D015699:HIV Envelope Protein gp120; D007375:Interleukin-1; D016328:NF-kappa B; D011506:Proteins; D011993:Recombinant Fusion Proteins; C486300:TAB1 protein, human; C410585:TAB2 protein, human; D048029:TNF Receptor-Associated Factor 6; D016212:Transforming Growth Factor beta; D011494:Protein Kinases; D053592:Interleukin-1 Receptor-Associated Kinases