title: PML plays both inimical and beneficial roles in HSV-1 replication.
abstract: After entry into the nucleus, herpes simplex virus (HSV) DNA is coated with repressive proteins and becomes the site of assembly of nuclear domain 10 (ND10) bodies. These small (0.1-1 μM) nuclear structures contain both constant [e.g., promyelocytic leukemia protein (PML), Sp100, death-domain associated protein (Daxx), and so forth] and variable proteins, depending on the function of the cells or the stress to which they are exposed. The amounts of PML and the number of ND10 structures increase in cells exposed to IFN-β. On initiation of HSV-1 gene expression, ICP0, a viral E3 ligase, degrades both PML and Sp100. The earlier report that IFN-β is significantly more effective in blocking viral replication in murine PML(+/+) cells than in sibling PML(-/-) cells, reproduced here with human cells, suggests that PML acts as an effector of antiviral effects of IFN-β. To define more precisely the function of PML in HSV-1 replication, we constructed a PML(-/-) human cell line. We report that in PML(-/-) cells, Sp100 degradation is delayed, possibly because colocalization and merger of ICP0 with nuclear bodies containing Sp100 and Daxx is ineffective, and that HSV-1 replicates equally well in parental HEp-2 and PML(-/-) cells infected at 5 pfu wild-type virus per cell, but poorly in PML(-/-) cells exposed to 0.1 pfu per cell. Finally, ICP0 accumulation is reduced in PML(-/-) infected at low, but not high, multiplicities of infection. In essence, the very mechanism that serves to degrade an antiviral IFN-β effector is exploited by HSV-1 to establish an efficient replication domain in the nucleus.
authors.affiliation: Marjorie B. Kovler Viral Oncology Labs, The University of Chicago, Chicago IL 60637.
authors.forename: Pei
authors.initials: P
authors.lastname: Xu
authors.affiliation: Marjorie B. Kovler Viral Oncology Labs, The University of Chicago, Chicago IL 60637.
authors.forename: Stephen
authors.initials: S
authors.lastname: Mallon
authors.affiliation: Marjorie B. Kovler Viral Oncology Labs, The University of Chicago, Chicago IL 60637 bernard.roizman@bsd.uchicago.edu.
authors.forename: Bernard
authors.initials: B
authors.lastname: Roizman
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D034961:Antigens, Nuclear / Q000235:genetics / Q000378:metabolism; D001324:Autoantigens / Q000235:genetics / Q000378:metabolism; D002522:Chlorocebus aethiops; D056970:Co-Repressor Proteins; D018259:Herpesvirus 1, Human / Q000502:physiology*; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism*; D016899:Interferon-beta / Q000235:genetics / Q000378:metabolism; D045586:Intranuclear Inclusion Bodies / Q000235:genetics / Q000378:metabolism* / Q000821:virology; D051379:Mice; D018832:Molecular Chaperones; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D000071156:Promyelocytic Leukemia Protein / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D014709:Vero Cells; D014779:Virus Replication / Q000502:physiology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D034961:Antigens, Nuclear; D001324:Autoantigens; C094297:CALCOCO2 protein, human; D056970:Co-Repressor Proteins; C106985:DAXX protein, human; D017874:Immediate-Early Proteins; D018832:Molecular Chaperones; D009687:Nuclear Proteins; D000071156:Promyelocytic Leukemia Protein; C066642:SP100 protein, human; C070576:PML protein, human; D016899:Interferon-beta; D044767:Ubiquitin-Protein Ligases; C051804:Vmw110 protein, Human herpesvirus 1
keywords: Daxx; ICP0; ND10; Sp100; interferon