The data presented here, show that ORF57-dependency is conferred by a high A/T content. This detrimental nucleotide bias of the KSHV lytic genes might be a strategy of the virus to maintain latency and to prevent accidental expression of its lytic genes, thereby preventing the host cell immune response. The nucleotide bias might constitute binding motifs for RBPs which negatively influence expression, for instance by preventing nuclear export. This is in line with other studies on HIV gag sequence optimisation (Kofman et al. 2003, Negumbela et al. 2008) arguing that improved expression after sequence optimisation is not due to tRNA availability or translational efficiency, but rather due to enhanced RNA stability and/or export.
During the lytic cycle ORF57 may not distinguish between cellular and vial transcripts but accepts the upregulation of cellular RNAs with a comparable nucleotide bias. A similar observation has also been made for the gammaherpesviral host shutoff endonuclease (SOX). During the host shutoff not only cellular RNAs are degraded, but
Discussion
also viral RNAs (Abernathy et al. 2014). For SOX, as for ORF57, it is likely that a cellular partner is involved in target RNA selection. Therefore, an interesting new approach for the near future could be the analysis of cellular RNAs that are upregulated in the presence of ORF57. This approach could give new hints about the exact motif that confers ORF57-dependency.
However, even if ORF57 does not distinguish between cellular and viral transcripts, it might achieve a degree of selectivity by using this unusual codon bias as a target sequence which is not frequent in cellular genes. The advantage of this strategy would be that on the one hand accidental expression of lytic genes would be prevented and on the other hand most cellular genes would not be influenced by ORF57.
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