Abstract
The Epstein-Barr virus (EBV)-encoded protein latent membrane protein 1 (LMP1) is essential for EBV-mediated B cell transformation and plays a critical role in the development of post-transplant B cell lymphomas. LMP1 also contributes to the exacerbation of autoimmune diseases such as systemic lupus erythematosus (SLE). LMP1 is a functional mimic of the tumor necrosis factor receptor (TNFR) superfamily member CD40, and relies on TNFR-associated factor (TRAF) adaptor proteins to mediate signaling. However, LMP1 activation signals to the B cell are amplified and sustained compared to CD40 signals. We previously demonstrated that LMP1 and CD40 use TRAF molecules differently. Although associating with CD40 and LMP1 via separate mechanisms, TRAF6 plays a significant role in signal transduction by both. It is unknown whether TRAF6 mediates CD40 versus LMP1 functions via distinct or shared pathways. In this study, we tested the hypothesis that TRAF6 uses the kinase TAK1 to trigger important signaling pathways following both CD40 and LMP1 stimulation. We determined that TAK1 was required for JNK activation and interleukin-6 (IL-6) production mediated by CD40 and LMP1, in both mouse and human B cells. Additionally, TRAF3 negatively regulated TRAF6-dependent, CD40-mediated TAK1 activation by limiting TRAF6 recruitment. This mode of regulation was not observed for LMP1 and may contribute to the dysregulation of LMP1 compared to CD40 signals.
Highlights
Epstein-Barr virus (EBV), the causative agent of infectious mononucleosis [1,2], latently infects .90% of humans [3]
TRAF6 is required for the activation of TAK1 and NF-kB by latent membrane protein 1 (LMP1) [12], we found that TAK1 inhibition had no detectable effect on the two molecular events of IkBa phosphorylation and degradation induced by CD40 or LMP1 (Fig. 3)
TRAF6 plays a critical role in signaling through both CD40 and LMP1, despite distinct mechanisms of association with the two molecules [12]
Summary
Epstein-Barr virus (EBV), the causative agent of infectious mononucleosis [1,2], latently infects .90% of humans [3]. EBV reactivation in immunocompromised individuals is strongly associated with various malignancies, most notably Burkitt’s lymphoma, Hodgkin’s disease, nasopharyngeal carcinoma, and post-transplant lymphomas/lymphoproliferative disease (PTLD) [2,3,4,5,6,7]. Transient EBV reactivation is observed in autoimmune diseases, especially systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) [9,10]. EBV preferentially establishes latency in memory B cells, but LMP1 is not expressed in infected cells unless EBV partially emerges from latency, usually in the context of immunosuppression or autoimmunity [1,7,11]. LMP1 is expressed in most EBV-associated malignancies and PTLD, and is required for EBV-mediated B cell transformation [12]. LMP1 has been implicated in the exacerbation of SLE [13,14]
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