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 necrosis factor receptor (TNFR)-associated factors (TRAFs) and the TNFR-associated death domain protein (TRADD). Moreover, it induces NF-kappaB and the c-Jun N-terminal kinase 1 (JNK1) pathway. Thus, LMP1 appears to mimick the molecular functions of TNFR1. However, TNFR1 elicits a wide range of cellular responses including apoptosis, whereas LMP1 constitutes a transforming protein. Here we mapped the JNK1 activator region (JAR) of the LMP1 molecule. JAR overlaps with the TRADD-binding domain of LMP1. In contrast to TNFR1, LMP1 recruits TRADD via the TRADD N-terminus but not the TRADD death domain. Consequently, the molecular function of TRADD in LMP1 signaling differs from its role in TNFR1 signal transduction. Whereas NF-kappaB activation by LMP1 was blocked by a dominant-negative TRADD mutant, LMP1 induces JNK1 independently of the TRADD death domain and TRAF2, which binds to TRADD. Further downstream, JNK1 activation by TNFR1 involves Cdc42, whereas LMP1 signaling to JNK1 is independent of p21 Rho-like GTPases. Although both LMP1 and TNFR1 interact with TRADD and TRAF2, the different topologies of the signaling complexes correlate with substantial differences between LMP1 and TNFR1 signal transduction to JNK1.
Kieser
A
A
Institute for Clinical Molecular Biology and Tumor Genetics, GSF-National Research Center for Environment and Health, Marchioninistrasse 25, D-81377 München, Germany.
Kaiser
C
C
Hammerschmidt
W
W
D015703:Antigens, CD / Q000378:metabolism*; D001665:Binding Sites; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002471:Cell Transformation, Neoplastic; D004789:Enzyme Activation; D020558:GTP Phosphohydrolases / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000378:metabolism; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D008954:Models, Biological; D008958:Models, Molecular; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism; D009856:Oncogene Proteins, Viral / Q000378:metabolism*; D011485:Protein Binding; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism*; D047888:Receptors, Tumor Necrosis Factor, Type I; D015398:Signal Transduction; D047990:TNF Receptor-Associated Factor 1; D047992:TNF Receptor-Associated Factor 2; D014763:Viral Matrix Proteins / Q000378:metabolism*; D020741:rho GTP-Binding Proteins
D015703:Antigens, CD; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D016328:NF-kappa B; D009856:Oncogene Proteins, Viral; D011506:Proteins; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D047990:TNF Receptor-Associated Factor 1; D047992:TNF Receptor-Associated Factor 2; D014763:Viral Matrix Proteins; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D020558:GTP Phosphohydrolases; D019204:GTP-Binding Proteins; D020741:rho GTP-Binding Proteins