Kaposi's Sarcoma Herpesvirus microRNAs Target Caspase 3 and Regulate Apoptosis

Guillaume Suffert, Georg Malterer, Jean Hausser, Johanna Viiliainen, Aurelie Fender, Maud Contrant, Tomi Ivacevic, Vladimir Benes, Frederic Gros, Olivier Voinnet, Mihaela Zavolan, Paivi M. Ojala, Juergen G. Haas, Sebastien Pfeffer

Research output: Contribution to journalArticlepeer-review

Abstract

Kaposi's sarcoma herpesvirus (KSHV) encodes a cluster of twelve micro (mi)RNAs, which are abundantly expressed during both latent and lytic infection. Previous studies reported that KSHV is able to inhibit apoptosis during latent infection; we thus tested the involvement of viral miRNAs in this process. We found that both HEK293 epithelial cells and DG75 cells stably expressing KSHV miRNAs were protected from apoptosis. Potential cellular targets that were significantly down-regulated upon KSHV miRNAs expression were identified by microarray profiling. Among them, we validated by luciferase reporter assays, quantitative PCR and western blotting caspase 3 (Casp3), a critical factor for the control of apoptosis. Using site-directed mutagenesis, we found that three KSHV miRNAs, miR-K12-1, 3 and 4-3p, were responsible for the targeting of Casp3. Specific inhibition of these miRNAs in KSHV-infected cells resulted in increased expression levels of endogenous Casp3 and enhanced apoptosis. Altogether, our results suggest that KSHV miRNAs directly participate in the previously reported inhibition of apoptosis by the virus, and are thus likely to play a role in KSHV-induced oncogenesis.

Original languageEnglish
Article numbere1002405
Pages (from-to)-
Number of pages18
JournalPLoS Pathogens
Volume7
Issue number12
DOIs
Publication statusPublished - Dec 2011

Keywords

  • Real-Time Polymerase Chain Reaction
  • Herpesvirus 8, Human
  • Apoptosis
  • Blotting, Northern
  • MicroRNAs
  • Oligonucleotide Array Sequence Analysis
  • Gene Expression Regulation, Viral
  • Humans
  • Caspase 3
  • Herpesviridae Infections
  • Mutagenesis, Site-Directed
  • In Situ Nick-End Labeling
  • Blotting, Western
  • Down-Regulation
  • Cell Line

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