TAK1‐binding protein 2 facilitates ubiquitination of TRAF6 and assembly of TRAF6 with IKK in the IL‐1 signaling pathway

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Abstract
TAK1 mitogen‐activated protein kinase kinase kinase participates in the Interleukin‐1 (IL‐1) signaling pathway by mediating activation of JNK, p38, and NF‐κB. TAK1‐binding protein 2 (TAB2) was previously identified as an adaptor that links TAK1 to an upstream signaling intermediate, tumor necrosis factor receptor‐associated factor 6 (TRAF6). Recently, ubiquitination of TRAF6 was shown to play an essential role in the activation of TAK1. However, the mechanism by which IL‐1 induces TRAF6 ubiquitination remains to be elucidated. Here we report that TAB2 functions to facilitate TRAF6 ubiquitination and thereby mediates IL‐1‐induced cellular events. A conserved ubiquitin binding domain in TAB2, the CUE domain, is important for this function. We also found that TAB2 promotes the assembly of TRAF6 with a downstream kinase, IκB kinase (IKK). These results show that TAB2 acts as a multifunctional signaling molecule, facilitating both IL‐1‐dependent TRAF6 ubiquitination and assembly of the IL‐1 signaling complex.