Interferon regulatory factor 7 mediates activation of Tap-2 by Epstein-Barr virus latent membrane protein 1

Transporter associated with antigen processing 2 (Tap-2) is responsible for ATP-dependent transport of peptides from the cytosol to the endoplasmic re ticulum, where peptides bind to newly synthesized human leukocyte antigen ( HLA) class I molecules, which are essential for cellular immune responses. Epstein-Barr virus (EBV) latent membrane protein I (LMP-1) has been shown t o induce the expression of Tap-2. In this study, the induction of endogenou s Tap-2 by LMP-1 is shown to be associated with and requires the expression of interferon regulatory factor 7 (IRF-7). In DG75 Burkitt's lymphoma (BL) cells, in which LMP-1 induces the expression of IRF-7, LMP-1 induced endog enous Tap-2, and ectopic expression of IRF-7 could enhance the induction. I n Akata BL cells, in which LMP-1 could not induce IRF-7, LMP-1 could not in duce Tap-2. Addition of IRF-7, which complements the defect in Akata cells, could stimulate the expression of Tap-2. Furthermore, LMP-1 and IRF-7A but not other IRF-7 splicing variants could activate endogenous Tap-2. A Tap-2 promoter reporter construct could be activated by the overexpression of IR F-7A. The activation could be specifically enhanced by LMP-1 and was depend ent on an intact interferon-stimulated response element (ISRE) present in t he Tap-2 promoter. Also, IRF-7 can bind to the Tap-2 promoter under physiol ogical conditions in vivo, as shown by formaldehyde cross-linking, as well as to the Tap-2 ISRE: In vitro, as shown by gel mobility shift assays. Furt hermore, LMP-1 facilitates the phosphorylation and nuclear translocation of IRF-7. These data point to the role of IRF-7 as a secondary mediator of LM P-l-activated signal transduction for Tap-2 as follows: LMP-1 stimulates th e expression of IRF-7 and facilitates its phosphorylation and nuclear trans location, and then the activated IRF-7 mediates the activation of the cellu lar Tap-2 gene. The induction of Tap-2 by IRF-7 and LMP-1 may have an impor tant implication for the immune response to EBV and its persistence in vivo .