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Kaposi's sarcoma (KS)-associated herpesvirus (KSHV)-encoded viral FLICE inhibitory protein (vFLIP) K13 is a potent activator of the nuclear factor-κB (NF-κB) pathway. In this study, we show that infection with KHSV and ectopic expression of K13, but not its NF-κB-defective mutant, suppressed the expression of CXCR4. Suppression of CXCR4 by KSHV and K13 was associated with upregulated expression of miR-146a, a microRNA that is known to bind to the 3′-untranslated region of CXCR4 mRNA. Reporter studies identified two NF-κB sites in the promoter of miR-146a that were essential for its activation by K13. Accordingly, ectopic expression of K13, but not its NF-κB-defective mutant or other vFLIPs, strongly stimulated the miR-146a promoter activity, which could be blocked by specific genetic and pharmacological inhibitors of the NF-κB pathway. Finally, expression of CXCR4 was downregulated in clinical samples of KS and this was accompanied by an increased expression of miR-146a. Our results show that K13-induced NF-κB activity suppresses CXCR4 through upregulation of miR-146a. Downregulation of CXCR4 expression by K13 may contribute to KS development by promoting premature release of KSHV-infected endothelial progenitors into the circulation. [ABSTRACT FROM AUTHOR]

Kaposi's sarcoma-associated herpesvirus (KSHV)-encoded viral FLICE inhibitory protein K13 interacts with a cytosolic IκB kinase (IKK) complex to activate nuclear factor-κB (NF-κB). We recently reported that K13 antagonizes KSHV lytic regulator RTA (replication and transcription activator) and blocks lytic replication, but spares RTA-induced viral interleukin-6 (vIL6). Here we report that K13 is also present in the nuclear compartment, a property not shared by its structural homologs. K13 interacts with and activates the nuclear IKK complex, and binds to the IκBα promoter. K13 mutants that are retained in the cytosol lack NF-κB activity. However, neither the IKKs nor NF-κB activation is required for nuclear localization of K13. Instead, this ability is dependent on a nuclear localization signal located in its N-terminal 40 amino acids. Finally, K13, along with p65/RelA, binds to the promoters of a number of KSHV lytic genes, including RTA, ORF57 and vGPCR, but not to the promoter of the vIL6 gene. Thus, K13 has an unexpected nuclear role in viral and cellular gene regulation and its differential binding to the promoters of lytic genes may not only contribute to the inhibition of KSHV lytic replication, but may also account for the escape of vIL6 from K13-induced transcriptional suppression.Oncogene (2008) 27, 5243–5253; doi:10.1038/onc.2008.150; published online 12 May 2008 [ABSTRACT FROM AUTHOR]