The Great Escape—How do Select RNAs Evade Degradation?

fishbowl comic

Although the vast majority of messages are degraded during lytic KSHV infection, we know that some transcripts escape degradation and accumulate robustly.  Prominent among these is human interleukin 6 (IL-6), a B cell growth factor that has been demonstrated to play a role in the pathogenesis of several KSHV-associated neoplasms.  By creating chimeric mRNAs, we have identified a specific element within IL-6 that renders it directly refractory to degradation by SOX (Hutin et al., J Virol 2013 Apr;87(8):4672-82).  We are in the process of identifying how factors that bind this element directly influence its susceptibility to SOX-induced cleavage.

Although IL-6 is the best-characterized escapee, microarray studies measuring host gene expression during lytic KSHV infection of microvascular endothelial cells indicated that other genes also escape host shutoff.  However, in the context of lytic infection a multitude of viral proteins likely influence cellular gene expression levels (either directly or indirectly), making it difficult to measure global susceptibility of mRNAs directly to SOX.  Using next generation deep sequencing, we were able to precisely delineate subsets of mRNAs that are either SOX targets or escapees. We confirmed that the majority of mRNAs are subject to SOX-induced turnover, although there exists a large population of transcripts that are not downregulated (Clyde and Glaunsinger, PLoS ONE. 2011 May 9;6(5):e19655).  While a significant proportion of these transcripts probably escape simply because they lack the cleavage element recognized by SOX, it is highly likely that some possess dominant protective elements akin to IL-6.  Identification of the dominant escapees and mechanisms involved in their stabilization is anticipated to reveal novel pathways and proteins involved in the intricate, yet poorly understood regulation of RNA turnover in both normal and pathogenic settings.