TTRAP, a novel protein that associates with CD40, tumor necrosis factor (TNF) receptor-75 and TNF receptor-associated factors (TRAFs), and that inhibits nuclear factor-kappa B activation.
CD40 belongs to the tumor necrosis factor (TNF) receptor family. CD40 signaling involves the recruitment of TNF receptor-associated factors (TRAFs) to its cytoplasmic domain. We have identified a novel intracellular CD40-binding protein termed TRAF and TNF receptor-associated protein (TTRAP) that also interacts with TNF-R75 and CD30. The region of the CD40 cytoplasmic domain that is required for TTRAP association overlaps with the TRAF6 recognition motif. Association of TTRAP with CD40 increases profoundly in response to treatment of cells with CD40L. Interestingly, TTRAP also associates with TRAFs, with the highest affinity for TRAF6. In transfected cells, TTRAP inhibits in a dose-dependent manner the transcriptional activation of a nuclear factor-kappaB (NF-kappaB)-dependent reporter mediated by CD40, TNF-R75 or Phorbol 12-myristate 13-acetate (PMA) and to a lesser extent by TRAF2, TRAF6, TNF-alpha, or interleukin-1beta (IL-1beta). TTRAP does not affect stimulation of NF-kappaB induced by overexpression of the NF-kappaB-inducing kinase (NIK), the IkappaB kinase alpha (IKKalpha), or the NF-kappaB subunit P65/RelA, suggesting it acts upstream of the latter proteins. Our results indicate that we have isolated a novel regulatory factor that is involved in signal transduction by distinct members of the TNF receptor family.
Pype
S
S
Department of Cell Growth, Flanders Interuniversity Institute for Biotechnology, Campus Gasthuisberg, University of Leuven, Herestraat 49, B-3000 Leuven, Belgium.
Declercq
W
W
Ibrahimi
A
A
Michiels
C
C
Van Rietschoten
J G
JG
Dewulf
N
N
de Boer
M
M
Vandenabeele
P
P
Huylebroeck
D
D
Remacle
J E
JE
D000595:Amino Acid Sequence; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D001426:Bacterial Proteins / Q000378:metabolism*; D019013:CD40 Antigens / Q000378:metabolism*; D017173:Caenorhabditis elegans; D002352:Carrier Proteins / Q000378:metabolism*; D003001:Cloning, Molecular; D006801:Humans; D051550:I-kappa B Kinase; D051379:Mice; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism*; D047889:Receptors, Tumor Necrosis Factor, Type II; D016415:Sequence Alignment; D015398:Signal Transduction; D048029:TNF Receptor-Associated Factor 6; D013755:Tetradecanoylphorbol Acetate / Q000378:metabolism; D051996:Transcription Factor RelA; D014981:Xenopus; D000097782:NF-kappaB-Inducing Kinase
D015703:Antigens, CD; D001426:Bacterial Proteins; D019013:CD40 Antigens; D002352:Carrier Proteins; D051550:I-kappa B Kinase; D016328:NF-kappa B; D017346:Protein Serine-Threonine Kinases; D011506:Proteins; D018124:Receptors, Tumor Necrosis Factor; D047889:Receptors, Tumor Necrosis Factor, Type II; D048029:TNF Receptor-Associated Factor 6; D013755:Tetradecanoylphorbol Acetate; D051996:Transcription Factor RelA; D000097782:NF-kappaB-Inducing Kinase; C496559:CHUK protein, human; C496564:Chuk protein, mouse; C496560:IKBKB protein, human; C496565:IKBKE protein, human; C496562:Ikbkb protein, mouse; C496566:Ikbke protein, mouse