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.