Inhibition of Host Gene Expression by KSHV: Sabotaging mRNA Stability and Nuclear Export

Abstract

Viruses are known for their ability to alter host gene expression. Kaposi sarcoma-associated herpesvirus has two proteins that obstruct host gene expression. KSHV SOX, encoded by the open reading frame 37 (ORF37), induces a widespread cytoplasmic mRNA degradation and a block on mRNA nuclear export. The other KSHV protein, encoded by the open reading frame 10 (ORF10), was recently identified to inhibit host gene expression through its direct function on the cellular mRNA export pathway. In this review, we summarize the studies on both SOX and ORF10 in efforts to elucidate their mechanisms. We also discuss how the findings based on a closely related rodent virus, murine gammaherpesvirus-68 (MHV-68), complement the KSHV findings to decipher the role of these two proteins in viral pathogenesis.

Keywords: Kaposi sarcoma-associated herpesvirus (KSHV); gammaherpesvirus; host gene expression inhibition; host mRNA nuclear export; mRNA stability; virus host interaction.

Figure 1

The inhibitory mechanisms of SOX and ORF10 proteins on host gene expression. SOX protein targets transcripts for degradation, affecting both the host and viral transcripts. On the other hand, ORF10 acts solely on cellular transcripts for export inhibition. Interestingly, both SOX and ORF10 cause the hyperadenylation of transcripts within the nucleus. (A) Cytoplasmic SOX protein, as encoded by ORF37, causes host shut off through its endonuclease activity. The viral endonucleolytic action on host transcript then triggers the cellular exonuclease, Xrn1, to complete transcript degradation. (B) At the nuclear envelope, ORF10 inhibits only the export of host transcripts by forming a complex with cellular export factor Rae1 and its partnering nucleoporin, Nup98. The hijacking of Rae1-Nup98 leads to nuclear retention of mRNAs. CBC, cap-binding complex; PABPC, cytoplasmic poly(A)-binding protein; PABPN, nuclear poly(A)-binding protein; PAPII, poly(A) polymerase II. Question marks indicate potential or hypothetical mechanisms and effects within the model.