Roles of TNF Receptor-Associated Factor 3 in Signaling to B Lymphocytes by Carboxyl-Terminal Activating Regions 1 and 2 of the EBV-Encoded Oncoprotein Latent Membrane Protein 1

摘要

TNFR-associated factor (TRAF)3,an adaptor protein that binds the cytoplasmic domains of both CD40 and the EBV-encoded oncoprotein latent membrane protein (LMP)l,is required for positive signaling by LMPl but not CD40 in B lymphocytes.The present study further investigated how TRAF3 participates in LMPl signaling.We found that TRAF3 mediates signaling both through direct interactions with the C-terminal activating region (CTAR)l of LMPl and through indirect interactions with the CTAR2 region of LMPl in mouse B cells.Notably,our results demonstrated that the CTAR2 region appears to inhibit the recruitment of TRAF1 and TRAF2 to membrane rafts by the CTARl region.Additionally,the absence of TRAF2 in B cells resulted in only a modest reduction in CTARl-mediated signals and no detectable efFect on CTAR2-mediated signals.CTARl and CTAR2 cooperated to achieve the robust signaling activity of LMPl when recruited to the same membrane microdomains in B cells.Interestingly,TRAF3 deficiency completely abrogated the cooperation between CTARl and CTAR2,supporting the hypothesis that TRAF3 participates in the physical interaction between CTARl and CTAR2 of LMPl.Together,our findings highlight the central importance of TRAF3 in LMPl-mediated signaling,which is critical for EBV persistent infection and EBV-associated pathogenesis.