THE (YXXL I)(2) SIGNALING MOTIF FOUND IN THE CYTOPLASMIC SEGMENTS OF THE BOVINE LEUKEMIA-VIRUS ENVELOPE PROTEIN AND EPSTEIN-BARR-VIRUS LATENT MEMBRANE PROTEIN-2A CAN ELICIT EARLY AND LATE LYMPHOCYTE-ACTIVATIONEVENTS/

The cytoplasmic domains of the transducing subunits associated with B and T cell antigen receptors contain a common amino acid motif consist ing of two precisely spaced Tyr-X-X-Leu/Ile sequences (where X corresp onds to a variable residue). Expression of a single copy of this motif suffices to initiate B or T cell activation. The bovine leukaemia vir us (BLV) is a B cell lymphotropic retrovirus which causes a non-neopla sic proliferation of B cells. The cytoplasmic domain of the BLV transm embrane envelope glycoprotein, gp30, possesses two overlapping copies of the Tyr-X-X-Leu/Ile-containing motif which could participate in the induction of B cell activation. Similarly, the N-terminal cytoplasmic domain of the latent membrane protein 2A (LMP2A) of the Epstein-Barr virus (EBV) contains a single copy of the Tyr-X-X-Leu/Ile-containing m otif which could play a critical rote in B cell transformation. To det ermine whether these two virus-encoded cytoplasmic domains are endowed with signalling functions, we constructed chimeric proteins by replac ing the cytoplasmic tail of CD8-alpha with that of either BLV gp30 or EBV LMP2A. We show here that, once separately expressed in B or T cell lines, these chimeras are capable of triggering both calcium response s and cytokine production when cross-linked with an antibody to CD8-al pha. Furthermore, using site-directed mutagenesis, we demonstrated une quivocally that this signalling function may be accounted for by the T yr-X-X-Leu/Ile motifs they contain. Since antibodies against the BLV e nvelope protein persist throughout infection, and LMP2A patches coloca lize with the latent membrane protein 1 (LMP1), our data suggest that oligomerization of these viral proteins may trigger the activation and proliferation of infected B cells and contribute to virus persistence .