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Background  In its RING domain, tumor necrosis factor receptor-associated factor 6 (TRAF6) has ubiquitin E3 ligase activity that facilitates the formation of lysine 63-linked polyubiquitin chains. This activity is required to activate nuclear factor  κ -light-chain-enhancer of activated B cells (NF- κ B) and plays an important role in the IκB kinase (IKK) complex.    Methods  An in vitro ubiquitination assay was used to establish whether c-Cbl could promote TRAF6 ubiquitination. We assessed direct binding and performed fine mapping between c-Cbl and TRAF6 based on the results of an immunoprecipitation assay with cultured 293 T cells. The luciferase reporter assay was applied to establish if c-Cbl-mediated ubiquitination affected NF- κ B activation after stimulus from various TRAF-mediated signals: tumor necrosis factor- α  (TNF- α ), receptor activator of NF- κ B ligand (RANKL), and interleukin-1 β  (IL-1 β ). An in vivo ubiquitination assay was performed using endogenous immunoprecipitation of TRAF6 in bone marrow macrophages (BMMs) and osteoclasts.    Results  Here, we report on a form of TRAF6 ubiquitination that is mediated by c-Cbl, leading to the formation of lysine 48-linked polyubiquitin chains. The NF- κ B activity induced by RANKL and IL-1 β  treatment is inhibited when c-Cbl is overexpressed, while the NF- κ B activity induced by TNFα treatment is not. c-Cbl inhibits NF- κ B activity mediated by TRAF6, but not by TRAF2. These findings show that c-Cbl ubiquitin ligase activity is essential for TRAF6 ubiquitination and negative regulation of NF- κ B activity. Fine mapping revealed that the proline-rich domain of c-Cbl is critical for interaction with TRAF6. Stimulation with RANKL or interferon- γ  (IFN- γ ) caused c-Cbl to bind to polyubiquitinated TRAF6.    Conclusions  These findings indicate that the interaction of TRAF6 with c-Cbl causes lysine 48-linked polyubiquitination for both negative feedback regulation and signaling cross-talk between RANKL and IFN- γ .

C-Cbl negatively regulates TRAF6-mediated NF-κB activation by promoting K48-linked polyubiquitination of TRAF6