The atypical PKC-interacting protein p62 channels NF-kappa B activation by the IL-1-TRAF6 pathway

Abstract

The atypical protein kinase C (aPKC)-interacting protein, p62, has previously been shown to interact with RIP, linking these kinases to NF-κB activation by tumor necrosis factor α (TNFα). The aPKCs have been implicated in the activation of IKKβ in TNFα-stimulated cells and have been shown to be activated in response to interleukin-1 (IL-1). Here we demonstrate that the inhibition of the aPKCs or the down-regulation of p62 severely abrogates NF-κB activation by IL-1 and TRAF6, suggesting that both proteins are critical intermediaries in this pathway. Consistent with this we show that p62 selectively interacts with the TRAF domain of TRAF6 but not that of TRAF5 or TRAF2 in co-transfection experiments. The binding of endogenous p62 to TRAF6 is stimulus dependent, reinforcing the notion that this is a physiologically relevant interaction. Furthermore, we demonstrate that the N-terminal domain of TRAF6, which is required for signaling, interacts with ζPKC in a dimerization-dependent manner. Together, these results indicate that p62 is an important intermediary not only in TNFa but also in IL-1 signaling to NF-κB through the specific adapters RIP and TRAF6.