Herpes Simplex Viruses (HSV-1 and 2) are endemic in the population and are responsible for oral and genital infections, sight-threatening ocular infections and encephalitis which can be life threatening even in immunocompetent adults. Our goal is to gain a better understanding of genome cleavage and packaging reactions in Herpes Simplex Virus type 1 (HSV-1), which are likely to involve dynamic interactions between multiple viral and cellular gene products.
We aim to investigate viral and host protein-protein interactions that contribute to this process using an interdisciplinary approach involving genetics, molecular biology, biochemistry, cell biology, biophysics and structural biology. The fact that HSV is amenable to both genetic and biochemical manipulation makes it an outstanding system to explore aspects of macromolecular assembly. We propose to continue our studies on viral gene products already implicated in encapsidation (terminase and portal) and also pursue recently identified connections between viral components and host cell molecular chaperones. These studies should not only further our understanding of this important biological process but also provide attractive and novel targets for therapeutic intervention of herpesviral infections.
Specific aims are: 1: To continue structure-function analysis of terminase subunits by mapping regions of terminase subunits (UL15 and UL28) responsible for protein-protein interactions, assembly into capsids and localization to appropriate locations within the infected cell. 2. To use genetic, biophysical and structural approaches to map regions of UL6 needed for interaction of the portal protein (UL6) with terminase and capsid and to probe UL6-UL6 interactions leading to portal ring formation. 3. Test hypothesis that host cell chaperones such as pdi, hsc40, hsc70 and hps90 play a role in the function of UL6 and other viral proteins required for assembly and function of the cleavage/packaging machinery. 4. Test hypothesis that UL32 is a redox-sensitive chaperone-like protein needed for proper localization or assembly of the cleavage/packaging machinery in capsids.
|Albright, Brandon S; Kosinski, Athena; Szczepaniak, Renata et al. (2015) The putative herpes simplex virus 1 chaperone protein UL32 modulates disulfide bond formation during infection. J Virol 89:443-53|
|Szczepaniak, Renata; Nellissery, Jacob; Jadwin, Joshua A et al. (2011) Disulfide bond formation contributes to herpes simplex virus capsid stability and retention of pentons. J Virol 85:8625-34|
|Albright, Brandon S; Nellissery, Jacob; Szczepaniak, Renata et al. (2011) Disulfide bond formation in the herpes simplex virus 1 UL6 protein is required for portal ring formation and genome encapsidation. J Virol 85:8616-24|
|Weller, Sandra K (2010) Herpes simplex virus reorganizes the cellular DNA repair and protein quality control machinery. PLoS Pathog 6:e1001105|