Synergistic activation of interferon‐β gene transcription by the viral FLICE inhibitory protein of Kaposi's sarcoma‐associated herpesvirus and type I IFN activators

Abstract

Expression of Kaposi's sarcoma-associated herpesvirus v-FLIP leads to the spindle-shape morphology of endothelial cells and is essential for the survival of primary effusion lymphoma cells. Activation of the NF-kappaB transcription factor by v-FLIP is responsible for these effects. Considering that the interferon-beta (ifn-beta) gene is regulated partly through NF-kappaB, we sought to determine whether v-FLIP would activate the expression of the ifn-beta gene. Our results indicate that when v-FLIP is expressed by itself it has no effect on ifn-beta gene activation but when it is combined with known IFN-beta inducers, a synergistic activation of the ifn-beta gene occurs. This effect is strictly dependent on NF-kappaB and is mediated through the positive regulatory domain II of the IFN-beta promoter. Furthermore, we report that protection from Fas-induced cell-death by v-FLIP is observed whether or not the type I IFN signaling pathway is activated. Our work therefore contributes to increase our knowledge on v-FLIP, highlighting the complex immunomodulatory properties of this anti-apoptotic viral protein.