title: TRAF1 is a critical regulator of JNK signaling by the TRAF-binding domain of the Epstein-Barr virus-encoded latent infection membrane protein 1 but not CD40.
abstract: The oncogenic Epstein-Barr virus (EBV)-encoded latent infection membrane protein 1 (LMP1) mimics a constitutive active tumor necrosis factor (TNF) family receptor in its ability to recruit TNF receptor-associated factors (TRAFs) and TNF receptor-associated death domain protein (TRADD) in a ligand-independent manner. As a result, LMP1 constitutively engages signaling pathways, such as the JNK and p38 mitogen-activated protein kinases (MAPK), the transcription factor NF-kappaB, and the JAK/STAT cascade, and these activities may explain many of its pleiotropic effects on cell phenotype, growth, and transformation. In this study we demonstrate the ability of the TRAF-binding domain of LMP1 to signal on the JNK/AP-1 axis in a cell type- dependent manner that critically involves TRAF1 and TRAF2. Thus, expression of this LMP1 domain in TRAF1-positive lymphoma cells promotes significant JNK activation, which is blocked by dominant-negative TRAF2 but not TRAF5. However, TRAF1 is absent in many established epithelial cell lines and primary nasopharyngeal carcinoma (NPC) biopsy specimens. In these cells, JNK activation by the TRAF-binding domain of LMP1 depends on the reconstitution of TRAF1 expression. The critical role of TRAF1 in the regulation of TRAF2-dependent JNK signaling is particular to the TRAF-binding domain of LMP1, since a homologous region in the cytoplasmic tail of CD40 or the TRADD-interacting domain of LMP1 signal on the JNK axis independently of TRAF1 status. These data further dissect the signaling components used by LMP1 and identify a novel role for TRAF1 as a modulator of oncogenic signals.
authors.affiliation: Cancer Research UK Institute for Cancer Studies, The University of Birmingham Medical School, United Kingdom. A.G.Eliopoulos@bham.ac.uk
authors.forename: Aristides G
authors.initials: AG
authors.lastname: Eliopoulos
authors.forename: Elyse R
authors.initials: ER
authors.lastname: Waites
authors.forename: Sarah M S
authors.initials: SM
authors.lastname: Blake
authors.forename: Clare
authors.initials: C
authors.lastname: Davies
authors.forename: Paul
authors.initials: P
authors.lastname: Murray
authors.forename: Lawrence S
authors.initials: LS
authors.lastname: Young
mesh_terms: D001483:Base Sequence; D019013:CD40 Antigens / Q000737:chemistry / Q000378:metabolism*; D002460:Cell Line; D017931:DNA Primers; D004789:Enzyme Activation; D004854:Herpesvirus 4, Human / Q000378:metabolism*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D011506:Proteins / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D047990:TNF Receptor-Associated Factor 1; D014763:Viral Matrix Proteins / Q000737:chemistry / Q000378:metabolism*
chemical_list: D019013:CD40 Antigens; D017931:DNA Primers; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D011506:Proteins; D047990:TNF Receptor-Associated Factor 1; D014763:Viral Matrix Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases