For example, endogenous PIDD may escape as a consequence of transcriptional upregulation, even though the mRNA may remain susceptible to turnover by SOX, as observed during overexpression. Furthermore, this sort of dysregulation could account for the subset of mRNAs that are more highly expressed in the presence of muSOX relative to SOX, as muSOX may result in even greater damage due its stronger shutoff activity in these cells. If this is the case, it will be Staurosporine supply interesting to determine whether the virus exploits or compensates for a potentially widespread dysregulation of mRNA biogenesis. Moreover, this may also confound identification of commonalities among ����escapees���� and could explain our failure to detect shared traits beyond a trend toward degradation of more abundant messages. We have established that, contrary to lytic KSHV infection, there is no enrichment of ARE-bearing transcripts among those that escape shutoff by SOX alone, suggesting that another viral protein or a cellular response to other aspects of infection mediates this effect. Interestingly, both the IL-6 and AEN transcripts, which are not destabilized in the presence of SOX, bear AU-rich elements in their 39UTRs. Although it is unlikely that these AREs modulate stability during shutoff, there may be other attributes common to the escapee subset of AREbearing mRNAs, or highly regulated mRNAs in general, that promote escape from SOX-mediated degradation. Although SOX and muSOX target similar pools of mRNAs during shutoff, the mechanism of AEN transcript escape appears to be distinct for each factor. The reason for this difference is unclear. It is possible that AEN escapes destabilization in the presence of both factors when it is present at low levels, but at high levels becomes sensitive to the stronger shutoff factor muSOX, due to a slightly different mechanism of targeting. Alternatively, endogenous AEN may escape muSOX by the mechanism we propose for PIDD, in which dysregulation of accumulation of normally highly regulated mRNAs counteracts the loss to shutoff, which would not influence expression from a noncellular promoter. Host shutoff during a lytic KSHV infection in telomeraseimmortalized microvascular endothelial cells as determined by microarray occurs to a greater extent than in 293T cells expressing SOX alone. There are several possible Afatinib explanations for this observation. First, it is likely that additional viral factors contribute to shutoff in addition to SOX; indeed, other viral lytic genes such as RTA, ZTA and MTA affect transcription, splicing, export and stability of cellular mRNAs in diverse gammaherpesviruses including KSHV. Additionally, one or more other viral factors may be required for maximum shutoff activity by SOX by modulating its function or specifying its targets. Finally, it is possible that host shutoff by SOX occurs to varying degrees in different cell lineages, perhaps as a result of the availability of host factors that participate in SOX-mediated degradation.