ICP0 induces the accumulation of colocalizing conjugated ubiquitin.
Herpes simplex virus type 1 (HSV-1) immediate-early protein ICP0 is a general activator of viral gene expression which stimulates the initiation of lytic infection and reactivation from quiescence and latency. The importance of ICP0 to the biology of HSV-1 infection has stimulated interest in its mode of action. Previous studies have reported its interactions with other viral regulatory molecules, with the translation apparatus, with cyclin D3, and with a ubiquitin-specific protease. It has been demonstrated that ICP0 is able to induce the proteasome-dependent degradation of a number of cellular proteins, including components of centromeres and small nuclear substructures known as ND10 or PML nuclear bodies. ICP0 has a RING finger zinc-binding domain which is essential for its functions. In view of several recent examples of other RING finger proteins which modulate the stability of specific target proteins by acting as components of E3 ubiquitin ligase complexes, this study has explored whether ICP0 might operate via a similar mechanism. Evidence that the foci of accumulated ICP0 in transfected and infected cells contain enhanced levels of conjugated ubiquitin is presented. This effect was dependent on the RING finger region of ICP0, and comparison of the properties of a number of ICP0 mutants revealed an excellent correlation between previously established functions of ICP0 and its ability to induce concentrations of colocalizing conjugated ubiquitin. These results strongly support the hypothesis that a major factor in the mechanism by which ICP0 influences virus infection is its ability to induce the degradation of specific cellular targets by interaction with the ubiquitin-proteasome pathway.
Everett
R D
RD
MRC Virology Unit, Glasgow G11 5JR, Scotland, United Kingdom. r.everett@vir.gla.ac.uk
D020816:Amino Acid Motifs; D002460:Cell Line; D022003:Cell Nucleus Structures / Q000378:metabolism; D002503:Centromere / Q000378:metabolism; D003546:Cysteine Endopeptidases / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D015967:Gene Expression Regulation, Viral; D006561:Herpes Simplex / Q000821:virology; D018259:Herpesvirus 1, Human / Q000235:genetics / Q000502:physiology*; D017874:Immediate-Early Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D018613:Microscopy, Confocal; D009097:Multienzyme Complexes / Q000378:metabolism; D009154:Mutation; D009687:Nuclear Proteins / Q000378:metabolism; D010957:Plasmids; D046988:Proteasome Endopeptidase Complex; D014162:Transfection; D014407:Tumor Cells, Cultured; D044767:Ubiquitin-Protein Ligases; D014452:Ubiquitins / Q000737:chemistry* / Q000378:metabolism*; D016335:Zinc Fingers
D017874:Immediate-Early Proteins; D009097:Multienzyme Complexes; D009687:Nuclear Proteins; D014452:Ubiquitins; D044767:Ubiquitin-Protein Ligases; C051804:Vmw110 protein, Human herpesvirus 1; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex