The Epstein-Barr virus oncoprotein latent membrane protein 1 engages the tumor necrosis factor receptor-associated proteins TRADD and receptor-interacting protein (RIP) but does not induce apoptosis or require RIP for NF-kappaB activation.
A site in the Epstein-Barr virus (EBV) transforming protein LMP1 that constitutively associates with the tumor necrosis factor receptor 1 (TNFR1)-associated death domain protein TRADD to mediate NF-kappaB and c-Jun N-terminal kinase activation is critical for long-term lymphoblastoid cell proliferation. We now find that LMP1 signaling through TRADD differs from TNFR1 signaling through TRADD. LMP1 needs only 11 amino acids to activate NF-kappaB or synergize with TRADD in NF-kappaB activation, while TNFR1 requires approximately 70 residues. Further, LMP1 does not require TRADD residues 294 to 312 for NF-kappaB activation, while TNFR1 requires TRADD residues 296 to 302. LMP1 is partially blocked for NF-kappaB activation by a TRADD mutant consisting of residues 122 to 293. Unlike TNFR1, LMP1 can interact directly with receptor-interacting protein (RIP) and stably associates with RIP in EBV-transformed lymphoblastoid cell lines. Surprisingly, LMP1 does not require RIP for NF-kappaB activation. Despite constitutive association with TRADD or RIP, LMP1 does not induce apoptosis in EBV-negative Burkitt lymphoma or human embryonic kidney 293 cells. These results add a different perspective to the molecular interactions through which LMP1, TRADD, and RIP participate in B-lymphocyte activation and growth.
Department of Medicine, Brigham and Women's Hospital, and Channing Laboratories, Department of Microbiology and Molecular Genetics, Harvard Medical School, Boston, Massachusetts 02115-5804, USA.
K M
KM
Izumi
E D
ED
Cahir McFarland
A T
AT
Ting
E A
EA
Riley
B
B
Seed
E D
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Kieff
D015703:Antigens, CD / Q000502:physiology; D017209:Apoptosis; D001402:B-Lymphocytes / Q000378:metabolism / Q000473:pathology; D002051:Burkitt Lymphoma / Q000473:pathology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000502:physiology; D002461:Cell Line, Transformed; D002472:Cell Transformation, Viral; D005786:Gene Expression Regulation; D004854:Herpesvirus 4, Human / Q000502:physiology*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D019169:Jurkat Cells / Q000378:metabolism / Q000473:pathology; D007668:Kidney; D046911:Macromolecular Substances; D020928:Mitogen-Activated Protein Kinases; D008958:Models, Molecular; D016328:NF-kappa B / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism*; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology; D047888:Receptors, Tumor Necrosis Factor, Type I; D047990:TNF Receptor-Associated Factor 1; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D014763:Viral Matrix Proteins / Q000502:physiology*
D015703:Antigens, CD; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D046911:Macromolecular Substances; D016328:NF-kappa B; D011506:Proteins; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D047990:TNF Receptor-Associated Factor 1; D014763:Viral Matrix Proteins; C506249:RIPK1 protein, human; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases