Requirement for TRAF3 in signaling by LMP1 but not CD40 in B lymphocytes.
CD40, a member of the tumor necrosis factor receptor family, and the Epstein-Barr virus-encoded oncoprotein latent membrane protein 1 (LMP1) share several tumor necrosis factor receptor-associated factor (TRAF) adaptor proteins for signaling. Among these, TRAF3 was the first identified to directly bind both receptors, yet its role remains a mystery. To address this, we generated B cell lines deficient in TRAF3 by homologous recombination. We found that CD40 signals were normal in the absence of TRAF3, with the exception of moderately enhanced c-Jun NH2-terminal kinase (JNK) activation and antibody secretion. In sharp contrast, LMP1 signaling was markedly defective in TRAF3-/- B cells. LMP1-induced activation of JNK and nuclear factor kappaB, up-regulation of CD23 and CD80, and antibody secretion were substantially affected by TRAF3 deficiency. Reconstitution of TRAF3 expression decreased CD40-induced JNK activation and antibody secretion, and fully restored LMP1 signaling. Although TRAF2 is widely believed to be important for LMP1 function, LMP1 signaling was intact in TRAF2-/- B cells. Our data reveal that CD40 and LMP1 unexpectedly use TRAF3 in different ways, and that TRAF3 is required for LMP1-mediated activation of B cells.
Xie
Ping
P
Department of Microbiology, University of Iowa, Iowa City 52242, USA.
Hostager
Bruce S
BS
Bishop
Gail A
GA
D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000502:physiology* / Q000821:virology; D019013:CD40 Antigens / Q000502:physiology*; D002460:Cell Line; D018390:Gene Targeting; D004854:Herpesvirus 4, Human / Q000472:pathogenicity / Q000502:physiology; D051379:Mice; D011506:Proteins / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction; D047992:TNF Receptor-Associated Factor 2; D048008:TNF Receptor-Associated Factor 3; D014763:Viral Matrix Proteins / Q000502:physiology*
D019013:CD40 Antigens; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D011506:Proteins; D047992:TNF Receptor-Associated Factor 2; D048008:TNF Receptor-Associated Factor 3; D014763:Viral Matrix Proteins