CYCLOSPORINE A-SENSITIVE INDUCTION OF THE EPSTEIN-BARR-VIRUS LYTIC SWITCH IS MEDIATED VIA A NOVEL PATHWAY INVOLVING A MEF2 FAMILY MEMBER

Induction of the Epstein-Barr virus (EBV) lytic cycle by crosslinking surface immunoglobulin is inhibited by the immunosuppressants cyclospo rin A (CsA) and FK506. This correlates with the ability of CsA to inhi bit Ca2+-dependent transcription of the lytic cycle switch gene BZLF1. It is shown here that CsA sensitivity maps to three sites (ZIA, ZIB a nd ZID) that bind the serum response factor-related protein MEF2D. A s ynthetic promoter containing multiple copies of a MEF2D site from Zp, in conjunction with a CREB/AP-1 site (ZII) from Zp, exhibits CsA-sensi tive inducibility. Furthermore, the Zp MEF2D sites were functionally i nterchangable with MEF2 sites derived from heterologous promoters. Whi le no evidence of a NFAT family member binding to either the MEF2 or C REB/AP-1 sites was obtained, it could be demonstrated that CsA-sensiti ve induction of Zp was mediated by calcineurin and NFATc2 in synergy w ith either phorbol ester or especially with the EBV-induced Ca2+/calmo dulin-dependent kinase type IV/Gr. These studies identify Zp as protot ypic of a novel class of CsA-sensitive and NFAT-dependent promoters de fined by the presence of MEF2 sites.