Kaposi's sarcoma-associated herpesvirus-encoded viral FLICE inhibitory protein (vFLIP) K13 suppresses CXCR4 expression by upregulating miR-146a.
Kaposi's sarcoma (KS)-associated herpesvirus (KSHV)-encoded viral FLICE inhibitory protein (vFLIP) K13 is a potent activator of the nuclear factor-kappaB (NF-kappaB) pathway. In this study, we show that infection with KHSV and ectopic expression of K13, but not its NF-kappaB-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-kappaB sites in the promoter of miR-146a that were essential for its activation by K13. Accordingly, ectopic expression of K13, but not its NF-kappaB-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-kappaB 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-kappaB 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.
Punj
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Division of Hematology-Oncology, Department of Medicine, Hillman Cancer Center, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA 15213-1863, USA.
Matta
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H
Schamus
S
S
Tamewitz
A
A
Anyang
B
B
Chaudhary
P M
PM
D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000235:genetics*; D015536:Down-Regulation; D004730:Endothelium, Vascular / Q000821:virology; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D019288:Herpesvirus 8, Human / Q000235:genetics* / Q000472:pathogenicity; D006801:Humans; D008156:Luciferases / Q000235:genetics; D035683:MicroRNAs / Q000235:genetics*; D016328:NF-kappa B / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic; D019718:Receptors, CXCR4 / Q000235:genetics*; D012514:Sarcoma, Kaposi / Q000235:genetics* / Q000821:virology; D013489:Suppression, Genetic; D015854:Up-Regulation; D014764:Viral Proteins / Q000235:genetics
D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C527276:CXCR4 protein, human; C542542:MIRN146 microRNA, human; D035683:MicroRNAs; D016328:NF-kappa B; D019718:Receptors, CXCR4; D014764:Viral Proteins; C481275:viral FLIP protein, Human herpesvirus 8; D008156:Luciferases