期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：1999
卷号：96
期号：4
页码：1234-1239
DOI：10.1073/pnas.96.4.1234
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：CD40 signaling modulates the immune response at least in part by activation of nuclear factor {kappa}B (NF{kappa}B). It has been shown that two distinct domains in the CD40 cytoplasmic tail (cyt), namely cyt-N and cyt-C, independently activate NF{kappa}B. Although four members of the tumor necrosis factor receptor-associated factor (TRAF) family, including TRAF2, TRAF3, TRAF5, and TRAF6, bind to the CD40 cyt, how each TRAF protein contributes to the NF{kappa}B activation by CD40 is not clear. Here we report that TRAF2, TRAF3, and TRAF5 bind cyt-C, whereas TRAF6 binds cyt-N. cyt-N is conserved poorly between human and mouse CD40, while cyt-C is highly conserved. However, single aa substitution of Glu-235 in cyt-N of human CD40 with Ala abolishes the binding of TRAF6 to cyt-N and NF{kappa}B activation by cyt-N. Conservation of this Glu between mouse and human CD40 strongly suggests that TRAF6 could link cyt-N to signals essential for CD40-mediated immune response. Furthermore, NF{kappa}B activation by cyt-C is inhibited by a kinase-negative form of NF{kappa}B-inducing kinase more efficiently than that by cyt-N, consistent with the result that NF{kappa}B activation by TRAF2 and TRAF5 is inhibited by a kinase-negative form of NF{kappa}B-inducing kinase more efficiently than that by TRAF6. These results indicate that NF{kappa}B activating signals emanating from cyt-N and cyt-C are mediated by the different members of the TRAF family and could be regulated in a distinct manner.
