Identification of TRAF6, a Novel Tumor Necrosis Factor Receptor-associated Factor Protein That Mediates Signaling from an Amino-terminal Domain of the CD40 Cytoplasmic Region

• Published in: The Journal of biological chemistry Vol. 271; no. 46; pp. 28745 - 28748
• Main Authors: Ishida, Takaomi, Mizushima, Sei-ichi, Azuma, Sakura, Kobayashi, Norihiko, Tojo, Tadashi, Suzuki, Kimie, Aizawa, Shigemi, Watanabe, Toshiki, Mosialos, George, Kieff, Elliott, Yamamoto, Tadashi, Inoue, Jun-ichiro
• Format: Journal Article
• Language: English
• Published: United States American Society for Biochemistry and Molecular Biology 15.11.1996
• Subjects: Amino Acid Sequence; Animals; Carrier Proteins - chemistry; Carrier Proteins - metabolism; CD40 Antigens - metabolism; DNA, Complementary; Epstein-Barr virus; Humans; Jurkat Cells; Mice; Mice, Inbred C57BL; Molecular Sequence Data; NF-kappa B - metabolism; Protein Binding; Proteins; Signal Transduction; TNF Receptor-Associated Factor 6; Tumor Cells, Cultured
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.271.46.28745

CD40 signalings play crucial roles in B-cell function. To identify molecules which transduce CD40 signalings, we have utilized the yeast two-hybrid system to clone cDNAs encoding proteins that bind the cytoplasmic tail of CD40. A cDNA encoding a putative signal transducer, designated TRAF6, has been molecularly cloned. TRAF6 has a tumor necrosis factor receptor (TNFR)-associated factor (TRAF) domain in its carboxyl terminus and has a RING finger domain, a cluster of zinc fingers and a coiled-coil domain, which are also present in other TRAF family proteins. TRAF6 does not associate with the cytoplasmic tails of TNFR2, CD30, lymphotoxin-β receptor, and LMP1 of Epstein-Barr virus. Deletion analysis showed that residues 246-269 of CD40 which are required for its association with TRAF2, TRAF3, and TRAF5 are dispensable for its interaction with TRAF6, whereas residues 230-245 were required. Overexpression of TRAF6 activates transcription factor NFκB, and its TRAF-C domain suppresses NFκB activation triggered by CD40 lacking residues 246-277. These results suggest that TRAF6 could mediate the CD40 signal that is transduced by the amino-terminal domain (230-245) of the CD40 cytoplasmic region and appears to be independent of other known TRAF family proteins.