The EBV Latent Antigen 3C Inhibits Apoptosis through Targeted Regulation of Interferon Regulatory Factors 4 and 8

Epstein-barr virus (ebv) is linked to a broad spectrum of b-cell malignancies. ebv nuclear antigen 3c (ebna3c) is an encoded latent antigen required for growth transformation of primary human b-lymphocytes. interferon regulatory factor 4 (irf4) and 8 (irf8) are transcription factors of the irf family that regulate diverse functions in b cell development. irf4 is an oncoprotein with anti-apoptotic properties and irf8 functions as a regulator of apoptosis and tumor suppressor in many hematopoietic malignancies. we now demonstrate that ebna3c can contribute to b-cell transformation by modulating the molecular interplay between cellular irf4 and irf8. we show that ebna3c physically interacts with irf4 and irf8 with its n-terminal domain in vitro and forms a molecular complex in cells. we identified the spi-1/b motif of irf4 as critical for ebna3c interaction. we also demonstrated that ebna3c can stabilize irf4,which leads to downregulation of irf8 by enhancing its proteasome-mediated degradation. further,si-rna mediated knock-down of endogenous irf4 results in a substantial reduction in proliferation of ebv-transformed lymphoblastoid cell lines (lcls),as well as augmentation of dna damage-induced apoptosis. irf4 knockdown also showed reduced expression of its targeted downstream signalling proteins which include cdk6,cyclin b1 and c-myc all critical for cell proliferation. these studies provide novel insights into the contribution of ebna3c to ebv-mediated b-cell transformation through regulation of irf4 and irf8 and add another molecular link to the mechanisms by which ebv dysregulates cellular activities,increasing the potential for therapeutic intervention against ebv-associated cancers. © 2013 banerjee et al.