Herpes simplex virus type 1 and the unfolded protein response

Burnett, Heather F.
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University of Guelph

HSV-1 particles have evolved to manipulate infected cells and produce an environment conducive to viral gene expression, genome replication and particle packaging. To facilitate the massive quantities of proteins required by the virus, the unfolded protein response must be activated to upregulate molecular chaperone expression and increase the folding capacity of the cell. A careful balance has evolved that allows viruses to specifically upregulate favorable pathways, while downregulating those that are less desirable. This thesis identifies the viral immediate early gene ICP0 as a key regulator of the UPR. Infected cells augment the expression of three 'cis'-acting elements, UPRE, ERSE, and ERSE-II found in the promoters of several key ER stress-related genes. Using an IRE1 knockout cell line it was determined that activation through each of these elements was not only regulated by cellular factors, but also by the viral gene ICP0 throughout the course of infection. Analysis of genes regulated by the UPR identified a marked dephosphorylation in the [alpha]-subunit of eukaryotic translation initiation factor 2 (eIF2[alpha]) repressing ER stress mediated translational attenuation, as well as an increase in ER chaperone proteins GRP78 and GRP94. As well, it was shown that the ICP0 promoter is responsive to ER stress signaling. This is achieved through mimicry of ER stress responsive genes, in particular UPRE. From this data it is clear that HSV-1 has evolved a mechanism to manipulate the UPR and specifically activate beneficiary pathways for the sake of augmenting productive viral infection. Luman is a HSV-1 related cellular protein that has been implicated in the UPR. Recently, rat C6 glial cells, a cell type known to resist HSV-1 infection, were found to have considerable levels of endogenous Luman protein. Stable Luman knockdown C6 cells were created in order to define this proteins biological role.

Herpes simplex virus, Type 1, Unfolded proteins, Regulator, ICPO