Translation Regulation by Enterovirus Proteinase

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The long term goal of this research is to understand the mechanism by which enteroviruses such as poliovirus (PV) and Coxsackievirus (CVB3) inactivate translation of nearly all cellular mRNA while stimulating efficient translation of viral mRNA in infected cells. We and others have shown that cleavage of the translation initiation factor elF4G will block assembly of new capped mRNA on ribosomes, and that cleavage of PABP is required in concert with e!F4G to cause drastic translation inhibition. PABP cleavage affects late steps in translation that are presently undefined, however cleavage likely interupts ribosome recycling via 5'- 3' interactions on mRNA. The mechanism of ribosome recycling and its biochemical requirements are unknown. In addition, enteroviruses and probably most other plus strand RNA viruses must abruptly shut down translation of the infecting viral genome before viral RNA synthesis can begin. We hypothesize that PABP cleavage is also required for inhibition of viral translation along with cleavage of key IRES transactivating factors. Translation regulation mechanisms involving elF4E, elF4G and PABP are now thought to interface with mRNA decay mechanisms on several levels. In addition, microRNAs, which bind to 3' UTR of targeted cellular mRNAs, also silence translation by unknown mechanisms that somehow result in transit of mRNAs from polysomes to other cell compartments called P-bodies and stress granules. We have discovered that G3BP, a key factor that nucleates formation of stress granules, is cleaved in PV-infected cells by 3C protease. Thus, the virus is attacking the overall translation regulatory apparatus at a new level. The aims in this proposal will determine the role of PABP cleavage in the switch from viral translation to RNA replication, will determine the role of ribosome recycling in this switch, and will investigate the function of G3BP cleavage on the viral replication cycle and microRNA-translation silencing. These results will provide new fundamental information how cells regulate gene expression at the translation level. We will learn more about the close interplay between translation initiation factors and mRNA silencing/decay pathways. We will elucidate why RNA viruses need to control the flow of mRNA from polysomes to stress granules. This new information will be useful in the broad areas of studies of viral regulation of gene expression, miRNA-mediated translation silencing, and cellular stress responses in cancer and apoptosis.