The herpes simplex virus (HSV) protein ICP34.5 is a virion component that forms a DNA-binding complex with proliferating cell nuclear antigen and HSV replication proteins.
The replicative ability of ICP34.5-null herpes simplex virus (HSV) is cell type and state dependent. In certain cells, ICP34.5 interacts with protein phosphatase 1 to preclude host cell protein synthesis shutoff by dephosphorylation of the eukaryotic initiation factor eIF-2alpha. However, host cell shutoff is not induced by ICP34.5-null HSV in most cells, irrespective of type and state. In general, dividing cells support replication of ICP34.5-null HSV; nondividing cells cannot. Previously the authors showed that ICP34.5 binds to proliferating cell nuclear antigen (PCNA), a protein necessary for cellular DNA replication and repair. Here the authors demonstrate that (1) the interaction between ICP34.5 and PCNA involves two regions of the virus protein; (2) ICP34.5 forms a complex with HSV replication proteins that is DNA binding; (3) at early times in infection, ICP34.5 colocalizes with PCNA and HSV replication proteins in cell nuclei, before accumulating in the cytoplasm; and (4) ICP34.5 is a virion protein. In light of ongoing clinical trials assessing the safety and efficacy of ICP34.5-null HSV, it is vital that the roles of ICP34.5 in HSV replication are understood. The authors propose that in nondividing cells, ICP34.5 is required to switch PCNA from repair to replication mode, a prerequisite for the initiation of HSV replication.
Harland
June
J
Glasgow University, Neurovirology Research Laboratories, Institute of Neurological Sciences, Southern General Hospital, Glasgow, United Kingdom.
Dunn
Paul
P
Cameron
Euan
E
Conner
Joe
J
Brown
S Moira
SM
D000818:Animals; D000906:Antibodies; D015153:Blotting, Western; D002467:Cell Nucleus / Q000821:virology; D002478:Cells, Cultured; D006224:Cricetinae; D003593:Cytoplasm / Q000821:virology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism; D006561:Herpes Simplex / Q000821:virology*; D007668:Kidney / Q000166:cytology; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism*; D018139:Simplexvirus / Q000235:genetics / Q000254:growth & development* / Q000378:metabolism*; D014760:Viral Fusion Proteins / Q000235:genetics / Q000378:metabolism; D014764:Viral Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D014771:Virion / Q000378:metabolism; D014779:Virus Replication / Q000502:physiology
D000906:Antibodies; D004268:DNA-Binding Proteins; D018809:Proliferating Cell Nuclear Antigen; D014760:Viral Fusion Proteins; D014764:Viral Proteins; C066469:gamma 34.5 protein, Human herpesvirus 1; D004259:DNA-Directed DNA Polymerase