EPSTEIN-BARR-VIRUS LATENT MEMBRANE PROTEIN-1 (LMP1) SIGNALING IS DISTINCT FROM CD40 AND INVOLVES PHYSICAL COOPERATION OF ITS 2 C-TERMINUS FUNCTIONAL REGIONS

The Epstein-Barr virus (EBV) encoded Latent Membrane Protein-1 (LMP1) mimics a constitutively active receptor molecule, and has been shown t o activate NF-kappa B and the MAPK and JNK pathways, Two regions withi n the cytosolic domain of LMP1 have been found to effect cell signalli ng. One of these, the carboxy-terminal activation region-1 (CTAR1), bi nds members of the TRAF family of proteins, and the other (CTAR2) bind s TRADD, suggesting that LMP1 transduces signals similarly to the Tumo ur Necrosis Factor Receptor family of receptors, The ability to bind T RAFs, to activate NF-kappa B and the JNK pathway, to upregulate cellul ar genes such as CD54 (ICAM-1 adhesion molecule), and to affect cell g rowth and apoptosis has led to the suggestion that LMP1 signalling is similar to, or even identical to CD40, However, we now show that while ligand-induced CD40 signalling is impaired in the Jurkat T cell line, LMP1 was fully functional; therefore demonstrating that LMP1 and CD40 signalling differ, Mutated LMP1 genes, in which one or other of the C TAR1 and CTAR2 domains was non-functional, behaved more like CD40 in b eing unable to upregulate the CD54 cell surface marker in Jurkat cells , However, the CTAR1 domain of LMP1, which shared a TRAF-binding seque nce motif with CD40, differed from CD40 in being unable to activate NF -kappa B in Jurkat, Cotransfection experiments with LMP1 mutants demon strated that CTAR1 can cooperative with CTAR2 on separate LMP1 molecul es, provided that they exist within the same oligomeric complex.