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

TitleThe atypical PKC-interacting protein p62 channels NF-kappaB activation by the IL-1-TRAF6 pathway.
Publication TypeJournal Article
Year of Publication2000
AuthorsSanz L, Diaz-Meco MT, Nakano H, Moscat J
JournalEMBO J
Date Published2000 Apr 03
KeywordsAdaptor Proteins, Signal Transducing, Antigens, Differentiation, Binding Sites, Cell Line, Humans, Interleukin-1, Interleukin-1 Receptor-Associated Kinases, Myeloid Differentiation Factor 88, NF-kappa B, Peptide Mapping, Protein Binding, Protein Kinase C, Protein Kinases, Protein Structure, Tertiary, Proteins, Receptors, Immunologic, Recombinant Proteins, Signal Transduction, TNF Receptor-Associated Factor 6

The atypical protein kinase C (aPKC)-interacting protein, p62, has previously been shown to interact with RIP, linking these kinases to NF-kappaB activation by tumor necrosis factor alpha (TNFalpha). The aPKCs have been implicated in the activation of IKKbeta in TNFalpha-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-kappaB 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 zetaPKC in a dimerization-dependent manner. Together, these results indicate that p62 is an important intermediary not only in TNFalpha but also in IL-1 signaling to NF-kappaB through the specific adapters RIP and TRAF6.

Alternate JournalEMBO J
PubMed ID10747026
PubMed Central IDPMC310227
Related Faculty: 
Jorge Moscat, Ph.D. Maria Diaz-Meco Conde, Ph.D.

Pathology & Laboratory Medicine 1300 York Avenue New York, NY 10065 Phone: (212) 746-6464
Surgical Pathology: (212) 746-2700