HSV molecular biology
HSV capsids going to nuclear pores early after infection
Group leader - Professor Peter O'Hare
Herpesviruses comprise a large family of double-stranded DNA viruses, sharing the morphologically defining features of an icosahedral capsid, in which the genome is packaged, surrounded by an amorphous layer of proteins termed the tegument, finally surrounded by a lipid envelope. They are classified into three subfamilies, the alpha, beta and gamma herpesviruses, based on both cell-type specificity and pathogenesis, and genome comparison. The genomes range in size from approximately 120kb to 250kb and encode from 70 to over 200 genes. Humans can be infected by eight different types of herpesvirus, with outcomes ranging from subclinical or relatively benign infections to extremely severe and even life-threatening, particularly in newborns or immunocompromised individuals.
While there are major differences in the replicative strategies of different herpesviruses, key features of replication and virus-host interactions are shared by all members, including the capacity to establish a latent infection, frequently for the lifetime of the infected individual, from which periodic reactivation and infection may occur. All herpesviruses also share major features of the replication cycle at the cellular level: they infect susceptible cells by fusion between virus encoded glycoproteins and host cell receptors at the plasma membrane or after endocytosis; infecting capsids travel to and dock at nuclear pores for genome transport to the nucleus; virus-encoded proteins coordinately regulate expression at the transcriptional and post-transcriptional levels; genomes are replicated and packaged into newly formed capsids in the nucleus; assembled capsids exit the nucleus, acquire additional proteins of the tegument in the cytoplasm, and finally are wrapped in a lipid envelope to form infectious progeny virions.
- We aim to understand some of the fundamental virus-host interactions underpinning key stages in the herpesvirus life cycle, focusing on herpes simplex virus. We also exploit virus–host interactions to probe cellular processes particularly in gene regulation, protein trafficking and modification, and nuclear organisation.
- We are exploring the converging interests of virus entry and assembly with the analysis of the nuclear pore and inner nuclear membrane/lamina organization. We are utilising combined approaches of genetics, biochemistry and imaging to dissect critical pathways at the earliest stages of infection and as progeny capsids traffic out of the nucleus, with a particular focus on the role of a novel virus encoded ubiqutin specific protease.
- We aim to understand the role of virus proteins in controlling the temporal transcriptional regulation of virus genes and the modulation, modification or degradation of host cell factors that provide structural or regulatory barriers to infection. Stemming originally from our analysis of virus transcription processes, we identified a novel class of cellular transmembrane transcription factors and are exploring the role of these proteins in the control of ER homeostasis, the monitoring and modelling of the secretory apparatus, in particular for specialised cargos, and the orchestration of appropriate responses to both environmental stresses and differentiation signals.
Selected references
Barbosa,S., Fasanella,I., Carriera,S., Llarena, M. Fox, R., Barreca,C., Andrew, D. and O’Hare, P. An orchestrated programme regulating secretory pathway genes and cargos by the transmembrane transcription factor CREB-H. (2013) Traffic 14: 382-398
Abaitua F, Bolstad M, Hollinshead M, Colin CM and O’Hare P. A nuclear localisation signal in the herpesvirus protein VP1-2 is essential for infection via capsid routing to the nuclear pore. (2012) J.Virol., 86:8998-9014
Bolstad, M., Abaitua, F., Crump,C.M. and O’Hare P. Autocatalytic activity of the Ubiquitin Specific Protease domain of HSV-1 VP1-2. (2011) J.Virol. 85: 8736-8751
Abaitua F., Daikoku, T. Crump, C., Bolstad, Mand O’Hare P. A single mutation responsible for temperature sensitive entry and assembly defects in the VP1-2 protein of HSV (2011) J. Virol., 85: 2024-2036
Llarena M, Bailey D, Curtis H, O'Hare P. (2010) Different mechanisms of recognition and ER retention by transmembrane transcription factors CREB-H and ATF6. Traffic. 11:48-69.
Abaitua F, Souto RN, Browne H, Daikoku T, O'Hare P. (2009) Characterization of the herpes simplex virus (HSV)-1 tegument protein VP1-2 during infection with the HSV temperature-sensitive mutant tsB7. J Gen Virol. 90:2353-63.
Hofemeister H, O'Hare P. Nuclear pore composition and gating in herpes simplex virus-infected cells. (2008) J Virol. 82:8392-9.
Abaitua, F. and O'Hare, P. (2008) Identification of a highly conserved, functional nuclear localization signal within the N-terminal region of Herpes Simplex Virus Type 1 VP1-2 tegument protein. J. Virol., 82:5234-5244.
Morris, J.B., Hofemeister, H. and O’Hare, P. (2007) Herpes simplex virus infection induces phosphorylation and delocalization of emerin, a key inner nuclear membrane protein. J. Virol., 81:4429-4437.
Bailey D, Barreca C, O'Hare P. Trafficking of the bZIP transmembrane transcription factor CREB-H into alternate pathways of ERAD and stress-regulated intramembrane proteolysis.(2007) Traffic. 8:1796-814.
Barreca, C. and O’Hare, P. (2006) Characterisation of a potent refractory state and persistence of herpes simplex virus 1 in cell culture. J. Virol., 80:9171-9180.
Stirling, J. and O’Hare, P. (2006) CREB4, a transmembrane bZip transcription factor and potential new substrate for regulation and cleavage by S1P. Mol. Biol. Cell, 17:413-426.
Bailey, D. and O’Hare, P. (2005) Comparison of the SUMO-1 and ubiquitin conjugation pathways during the inhibition of proteasome activity with evidence of SUMO-1 recycling. Biochem. J., 392:271-281.
Mouzakitis, G., McLauchlan, J., Barecca, C., Kueltzo, L. and O’Hare, P. (2005) Characterisation of VP22 in herpes simplex virus infected cells. J.Virol., 79:12185-12198.
