title: Essential roles of K63-linked polyubiquitin-binding proteins TAB2 and TAB3 in B cell activation via MAPKs.
abstract: Polyubiquitination of proteins plays a critical role in the activation of immune cells. K63-linked polyubiquitin-binding proteins TGF-β-activated kinase 1 (TAK1)-binding protein (TAB)2 and TAB3 are implicated in NF-κB signaling via TAK1 activation. However, TAB2 alone is dispensable for NF-κB activation in embryonic fibroblasts, and the functional roles of TAB2 and TAB3 in immune cells has yet to be clarified. In this study, we demonstrate that TAB2 and TAB3 are essential for B cell activation leading to Ag-specific Ab responses, as well as B-1 and marginal zone B cell development. TAB2 and TAB3 are critical for the activation of MAPKs, especially ERK, but not NF-κB, in response to TLR and CD40 stimulation in B cells. Surprisingly, TAB2 and TAB3 are dispensable for TAK1 activation in B cells, indicating that TAB2 and TAB3 activate MAPKs via a pathway independent of TAK1. In contrast to B cells, macrophages lacking TAB2 and TAB3 did not show any defects in the cytokine production and the signaling pathway in response to TLR stimulation. Furthermore, TAB2 and TAB3 were dispensable for TNF-induced cytokine production in embryonic fibroblasts. Thus, TAB2- and TAB3-mediated K63-linked polyubiquitin recognition controls B cell activation via MAPKs, but not the TAK1/NF-κB axis.
authors.affiliation: Laboratory of Infection and Prevention, Institute for Virus Research, Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Ori
authors.forename: Hiroki
authors.initials: H
authors.lastname: Kato
authors.forename: Hideki
authors.initials: H
authors.lastname: Sanjo
authors.forename: Sarang
authors.initials: S
authors.lastname: Tartey
authors.forename: Takashi
authors.initials: T
authors.lastname: Mino
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.forename: Osamu
authors.initials: O
authors.lastname: Takeuchi
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology; D002478:Cells, Cultured; D018985:Epitopes, B-Lymphocyte / Q000276:immunology; D005260:Female; D008213:Lymphocyte Activation / Q000276:immunology*; D020930:MAP Kinase Kinase Kinases / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D025821:Polyubiquitin / Q000737:chemistry / Q000378:metabolism*; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018985:Epitopes, B-Lymphocyte; D020930:MAP Kinase Kinase Kinases; D025821:Polyubiquitin; D000099151:MAP Kinase Kinase Kinase 7; C498761:Tab2 protein, mouse; C528083:Tab3 protein, mouse