Kaposi's sarcoma-associated herpesvirus ORF57 interacts with cellular RNA export cofactors RBM15 and OTT3 to promote expression of viral ORF59

Vladimir Majerciak, Hiroaki Uranishi, Michael Kruhlak, Guy R Pilkington, Maria Julia Massimelli, Jenifer Bear, George N Pavlakis, Barbara K Felber, Zhi-Ming Zheng

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Kaposi's sarcoma-associated herpesvirus (KSHV) encodes ORF57, which promotes the accumulation of specific KSHV mRNA targets, including ORF59 mRNA. We report that the cellular export NXF1 cofactors RBM15 and OTT3 participate in ORF57-enhanced expression of KSHV ORF59. We also found that ectopic expression of RBM15 or OTT3 augments ORF59 production in the absence of ORF57. While RBM15 promotes the accumulation of ORF59 RNA predominantly in the nucleus compared to the levels in the cytoplasm, we found that ORF57 shifted the nucleocytoplasmic balance by increasing ORF59 RNA accumulation in the cytoplasm more than in the nucleus. By promoting the accumulation of cytoplasmic ORF59 RNA, ORF57 offsets the nuclear RNA accumulation mediated by RBM15 by preventing nuclear ORF59 RNA from hyperpolyadenylation. ORF57 interacts directly with the RBM15 C-terminal portion containing the SPOC domain to reduce RBM15 binding to ORF59 RNA. Although ORF57 homologs Epstein-Barr virus (EBV) EB2, herpes simplex virus (HSV) ICP27, varicella-zoster virus (VZV) IE4/ORF4, and cytomegalovirus (CMV) UL69 also interact with RBM15 and OTT3, EBV EB2, which also promotes ORF59 expression, does not function like KSHV ORF57 to efficiently prevent RBM15-mediated nuclear accumulation of ORF59 RNA and RBM15's association with polyadenylated RNAs. Collectively, our data provide novel insight elucidating a molecular mechanism by which ORF57 promotes the expression of viral intronless genes.

Original languageEnglish
Pages (from-to)1528-40
Number of pages13
JournalJournal of Virology
Volume85
Issue number4
DOIs
Publication statusPublished - Feb 2011
Externally publishedYes

Keywords

  • Cell Nucleus/genetics
  • Cytoplasm/genetics
  • Gene Expression Regulation, Viral
  • HEK293 Cells
  • HeLa Cells
  • Herpesvirus 8, Human/genetics
  • Humans
  • Nucleocytoplasmic Transport Proteins/genetics
  • Open Reading Frames/genetics
  • RNA, Messenger/genetics
  • RNA, Viral/genetics
  • RNA-Binding Proteins/genetics
  • Viral Proteins/genetics

Cite this

Majerciak, V., Uranishi, H., Kruhlak, M., Pilkington, G. R., Massimelli, M. J., Bear, J., Pavlakis, G. N., Felber, B. K., & Zheng, Z-M. (2011). Kaposi's sarcoma-associated herpesvirus ORF57 interacts with cellular RNA export cofactors RBM15 and OTT3 to promote expression of viral ORF59. Journal of Virology, 85(4), 1528-40. https://doi.org/10.1128/JVI.01709-10