Identification of herpesvirus interactions at the nuclear envelope as potential targets for therapeutic intervention

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http://www.ed.ac.uk/biology/prospective-students/postgraduate/pgr/how-to-apply

Herpesviruses are a major health problem for both humans and animals. All herpesviruses are assembled in the nucleus and have to break through the nuclear envelope for infectivity. This step remains the least understood stage of the herpesvirus life cycle. Human herpesvirus 5 activates kinases to disassemble the nuclear lamina, a polymer that underlies the inner surface of the nuclear membrane1; however, after lamina disassembly the virus still must dock with the nuclear membrane to initiate budding. There are hundreds of transmembrane proteins in the nuclear envelope and we postulate that some might play roles in concentrating viral tegument proteins for assembly and/or in fusion with the membrane when the virus buds through the inner nuclear membrane. Regardless, these proteins need to be either used by the virus or removed by the virus for efficient egress. We are in a unique position to investigate this question as our proteomic studies of the nuclear envelope have identified hundreds of transmembrane proteins in this organelle2,3. Moreover, we have cloned 90 novel nuclear envelope transmembrane proteins (NETs) that we have already used in several functional screens2,3. The student will screen this set of NETs by confocal microscopy and Western blot in infected cells to identify any that colocalise with virus tegument proteins or change in localisation/levels that might thus contribute to herpesvirus assembly and egress through the nuclear envelope directly or indirectly. Candidate proteins will be further investigated by pulldowns for interactions with viral proteins and by knockdowns to determine the effect of their absence on infectivity