LMP1 signal transduction differs substantially from TNF receptor 1 signaling in the molecular functions of TRADD and TRAF2

The Epstein-Barr virus latent membrane protein 1 (LMP1) binds tumor necrosi s factor receptor (TNFR)-associated factors (TRAFs) and the TNFR-associated death domain protein (TRADD), Moreover, it induces NF-kappa B and the c-Ju n N-terminal kinase 1 (JNK1) pathway. Thus, LMP1 appears to mimick the mole cular functions of TNFR1, However, TNFR1 elicits a wide range of cellular r esponses including apoptosis, whereas LMP1 constitutes a transforming prote in, Here we mapped the JNK1 activator region (JAR) of the LMP1 molecule. JA R overlaps with the TRADD-binding domain of LMP1. In contrast to TNFR1, LMP 1 recruits TRADD via the TRADD N-terminus but not the TRADD death domain. C onsequently, the molecular function of TRADD in LMP1 signaling differs from its role in TNFR1 signal transduction. Whereas NF-kappa B activation by LM P1 was blocked by a dominant-negative TRADD mutant, LMP1 induces JNK1 indep endently of the TRADD death domain and TRAF2, which binds to TRADD, Further downstream, JNK1 activation by TNFR1 involves Cdc42, whereas LMP1 signalin g to JNK1 is independent of p21 Rho-like GTPases. Although both LMP1 and TN FR1 interact with TRADD and TRAF2, the different topologies of the signalin g complexes correlate with substantial differences between LMP1 and TNFR1 s ignal transduction to JNK1.