Differential TRAF3 utilization by a variant human CD40 receptor with enhanced signaling.
CD40 is required for T cell-dependent humoral immunity, but it can also contribute to the pathogenesis of autoimmunity and B cell malignancy. The TNFR-associated factor (TRAF)2 and TRAF6 adaptor proteins are positive regulators of CD40 signaling required to activate downstream kinase cascades and transcription factors. In contrast, TRAF3 can serve as a negative regulator of CD40 signaling, and CD40 signals are amplified in TRAF3(-/-) B cells. We previously reported a gain-of-function polymorphism of the human CD40 receptor, hCD40-P227A, which signals in an amplified manner to B lymphocytes. In this study, we show that hCD40-P227A binds more TRAF3 and TRAF5, as well as certain associated proteins, than wild-type-CD40. Studies in TRAF-deficient B cell lines revealed that hCD40-P227A uses TRAF3 as a positive rather than negative regulator. Although located outside of any known TRAF binding sites, the P227A polymorphism can alter TRAF binding and dramatically changes the role played by TRAF3 in CD40 signaling.
Medical Scientist Training Program and Immunology Graduate Program, University of Iowa, Iowa City, IA 52240, USA.
Anna L
AL
Peters
Gail A
GA
Bishop
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution / Q000235:genetics / Q000276:immunology; D000818:Animals; D001665:Binding Sites / Q000235:genetics / Q000276:immunology; D019013:CD40 Antigens / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002999:Clone Cells; D014644:Genetic Variation / Q000276:immunology*; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis; D051379:Mice; D008969:Molecular Sequence Data; D011110:Polymorphism, Genetic / Q000276:immunology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D048008:TNF Receptor-Associated Factor 3 / Q000172:deficiency / Q000378:metabolism* / Q000502:physiology; D048029:TNF Receptor-Associated Factor 6 / Q000172:deficiency / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology*
D019013:CD40 Antigens; C508600:IL6 protein, human; D015850:Interleukin-6; D048008:TNF Receptor-Associated Factor 3; D048029:TNF Receptor-Associated Factor 6; C090656:TRAF3 protein, human