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.

TAB3 involves in hepatic insulin resistance through activation of MAPK pathway

“…These results point to MAPK pathway as the possible link between TAB3 and insulin resistance. Furthermore, it appears that TAB3 is more critically required for activation of ERK than JNK and p38 MAPK, consistent with the results found in B cell (Ori et al, 2013), but the underlying mechanisms have yet to be unknown.…”

“…It is noteworthy that the decline in the phosphorylation of ERK with TAB3 siRNA was more significant than that of JNK or p38 under both normal and insulin-resistant conditions, suggesting that TAB3 might play a more important role in the activation of ERK than JNK or p38. These observations are consistent with the findings showing in B cells (Ori et al, 2013). All together, we believe that this provides a strong argument for the critical role of TAB3-derived activation of MAPKs in hepatic insulin resistance.…”

“…Most studies concentrate on the functions of two TAK1 complexes -TAK1 bound to TAB1 and TAB2/ TAB3. In fact, there are some evidences showing TAK1 complexes play a role in the activation of MAPK pathway (Mendoza et al, 2008;Ori et al, 2013). But the sole role of TAB3 is poorly understood.…”

Toll-Like Receptor Signaling Pathways

“…However, TLR4-mediated IKK, p38, and JNK activation and cytokine induction are increased in neutrophils derived from TAK1-deficient mice, suggesting a cell type-specific role for TAK1 in TLR signaling (47). Furthermore, the physiological roles of TAB proteins in TLR signaling also remain controversial: TAB1- or TAB2-deficient mice do not show any abnormality in TLR signaling pathways (48), and mice doubly deficient for TAB2 and TAB3 also exhibit normal cytokine production after TLR simulation in MEFs and macrophages (49). TAB family proteins may therefore compensate for each other in TLR signaling.…”

Essential Function for the Nuclear Protein Akirin2 in B Cell Activation and Humoral Immune Responses

“…Cell cycles of B cells were analyzed with a BrdU flow kit (BD Biosciences), as described previously (30). Briefly, splenocytes (1 3 10 6 ) were cultured in RPMI 1640 medium supplemented with 10% FCS and 50 mM 2-ME with various stimuli for 24 h, pulsed with 10 mM BrdU for an additional 16 h, stained with allophycocyanin-anti-CD19, FITC-anti-BrdU, and 7-aminoactinomycin D, and then analyzed by flow cytometry.…”