• Register
X
Forgot Password

If you have forgotten your password you can enter your email here and get a temporary password sent to your email.

X

Leaving Community

Are you sure you want to leave this community? Leaving the community will revoke any permissions you have been granted in this community.

No
Yes

Two differently regulated nuclear factor kappaB activation pathways triggered by the cytoplasmic tail of CD40.

CD40 signaling modulates the immune response at least in part by activation of nuclear factor kappaB (NFkappaB). It has been shown that two distinct domains in the CD40 cytoplasmic tail (cyt), namely cyt-N and cyt-C, independently activate NFkappaB. 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 NFkappaB 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 NFkappaB 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, NFkappaB activation by cyt-C is inhibited by a kinase-negative form of NFkappaB-inducing kinase more efficiently than that by cyt-N, consistent with the result that NFkappaB activation by TRAF2 and TRAF5 is inhibited by a kinase-negative form of NFkappaB-inducing kinase more efficiently than that by TRAF6. These results indicate that NFkappaB 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.

Pubmed ID: 9990007

Authors

  • Tsukamoto N
  • Kobayashi N
  • Azuma S
  • Yamamoto T
  • Inoue J

Journal

Proceedings of the National Academy of Sciences of the United States of America

Publication Data

February 16, 1999

Associated Grants

None

Mesh Terms

  • Amino Acid Sequence
  • Amino Acid Substitution
  • Animals
  • Antigens, CD40
  • Genes, Reporter
  • Humans
  • Jurkat Cells
  • Mice
  • Molecular Sequence Data
  • Mutagenesis, Site-Directed
  • NF-kappa B
  • Peptide Fragments
  • Proteins
  • Receptors, Tumor Necrosis Factor
  • Recombinant Fusion Proteins
  • Signal Transduction
  • TNF Receptor-Associated Factor 2
  • TNF Receptor-Associated Factor 3
  • TNF Receptor-Associated Factor 5
  • TNF Receptor-Associated Factor 6
  • Transfection