The Human Herpesvirus 8 Homolog of Epstein-Barr Virus SM Protein (KS-SM) Is a Posttranscriptional Activator of Gene Expression

Abstract

Homologs of the Epstein-Barr virus (EBV) SM protein exist in several human and nonhuman herpesviruses.Structure and function differ significantly among these proteins. We have cloned and characterized the human herpesvirus 8 (HHV8) gene, KS-SM, which is homologous to the EBV SM and herpes simplex virus ICP27 genes, from an HHV8-infected primary effusion lymphoma. KS-SM is shown to be a posttranscriptional activator of gene expression in cotransfection studies. KS-SM activated gene expression in a gene-specific, promoter-independent manner. In particular, KS-SM enhanced the expression of KDR/flk-1, a receptor for vascular endothelial growth factor (VEGF), in cotransfection studies. Since expression of KDR/flk-1 is increased in Kaposi's sarcoma and HHV8-infected cell cultures and VEGF enhances the proliferation of HHV8-infected cells, KS-SM may play a pathogenic role in Kaposi's sarcoma.

Rhesus Monkey Rhadinovirus ORF57 Induces gH and gL Glycoprotein Expression through Posttranscriptional Accumulation of Target mRNAs

“…The enhanced levels of gH and gL RNAs were not due to increased RNA synthesis. We confirmed that RRV ORF57 does not affect de novo transcription from a CMV promoter, which also has been observed for other ORF57s in previous reports (14,20).…”

“…8) seems to be best explained by the posttranscriptional stabilization of target RNA in the nucleus and subsequent nuclear egress of that RNA. The notion of nuclear stabilization agrees well with the cellular localization of ORF57, which resides principally in the nucleus (14,20,34). Also, the stabilization of target RNA in the nucleus by ORF57 has been well documented for KSHV PAN RNA (35).…”

“…RRV ORF57 did not activate the transcription of the renilla luciferase gene driven from the same CMV promoter (data not shown). Furthermore, it has been shown in previous reports that KSHV ORF57 did not activate transcription from a CMV promoter (14,20). We therefore hypothesized that gH and gL mRNAs are naturally unstable and that ORF57 allows gH, gL, c.o.…”

“…The transcriptional activation of these promoters could be accomplished by ORF57 protein alone, or it could be further enhanced by the cooperation with the ORF50 gene product (also known as RTA) (20,28,33). However, as the name MTA (mRNA transcript accumulation) in KSHV implies, a posttranscriptional mechanism of activation by ORF57 orthologues has been studied and documented most extensively (4,14,21,29). It has been reported that increased expression appears to be achieved in many cases via the facilitation of the nuclear export of target mRNAs (4,6,8,29,41).…”

The Evolutionarily Conserved Kaposi's Sarcoma-associated Herpesvirus ORF57 Protein Interacts with REF Protein and Acts as an RNA Export Factor

“…Like ICP27, KSHV ORF57 protein predominantly localizes to the nucleus (21)(22)(23) and can shuttle between the nucleus and cytoplasm (23). A post-transcriptional mode of ORF57 action was suggested as its expression increased the accumulation of cytoplasmic mRNA (21,22).…”