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Role of nuclear factor Y in stress-induced activation of the herpes simplex virus type 1 ICP0 promoter.

ABSTRACT: Herpesviruses are characterized by the ability to establish lifelong latent infections and to reactivate periodically, leading to recurrent disease. The herpes simplex virus type 1 (HSV-1) genome is maintained in a quiescent state in sensory neurons during latency, which is characterized by the absence of detectable viral protein synthesis. Cellular factors induced by stress may act directly on promoters within the latent viral genome to induce the transcription of viral genes and trigger reactivation. In order to identify which viral promoters are induced by stress and elucidate the cellular mechanism responsible for the induction, we generated a panel of HSV-1 promoter-luciferase constructs and measured their response to heat shock. Of the promoters tested, those of ICP0 and ICP22 were the most strongly upregulated after heat shock. Microarray analysis of lytically infected cells supported the upregulation of ICP0 and ICP22 promoters by heat shock. Mutagenic analysis of the ICP0 promoter identified two regions necessary for efficient heat-induced promoter activity, both containing predicted nuclear factor Y (NF-Y) sites, at bases -708 and -75 upstream of the transcriptional start site. While gel shift analysis confirmed NF-Y binding to both sites, only the site at -708 was important for efficient heat-induced activity. Reverse transcription-PCR analysis of selected viral transcripts in the presence of dominant-negative NF-Y confirmed the requirement for NF-Y in the induction of the ICP0 but not the ICP22 promoter by heat shock in lytically infected cells. These findings suggest that the immediate-early ICP0 gene may be among the first genes to be induced during the early events in HSV-1 reactivation, that NF-Y is important for this induction, and that other factors induce the ICP22 promoter.

SUBMITTER: Kushnir AS

PROVIDER: S-EPMC2798407 | biostudies-literature | 2010 Jan

REPOSITORIES: biostudies-literature

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Role of nuclear factor Y in stress-induced activation of the herpes simplex virus type 1 ICP0 promoter.

Kushnir Anna S AS Davido David J DJ Schaffer Priscilla A PA

Journal of virology 20100101 1

Herpesviruses are characterized by the ability to establish lifelong latent infections and to reactivate periodically, leading to recurrent disease. The herpes simplex virus type 1 (HSV-1) genome is maintained in a quiescent state in sensory neurons during latency, which is characterized by the absence of detectable viral protein synthesis. Cellular factors induced by stress may act directly on promoters within the latent viral genome to induce the transcription of viral genes and trigger reacti ...[more]

PMID: 19828605

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Project description:UnlabelledInfected cell protein 0 (ICP0) of herpes simplex virus 1 (HSV-1) is a key regulator in both lytic and latent infections. In lytic infection, an important early event is the colocalization of ICP0 to nuclear domain 10 (ND10), the discrete nuclear bodies that impose restrictions on viral expression. ICP0 contains an E3 ubiquitin ligase that degrades promyelocytic leukemia protein (PML) and Sp100, two major components of ND10, and disperses ND10 to alleviate repression. We previously reported that the association between ICP0 and ND10 is a dynamic process that includes three steps: adhesion, fusion, and retention. ICP0 residues 245 to 474, defined as ND10 entry signal (ND10-ES), is a region required for the fusion step. Without ND10-ES, ICP0 adheres at the ND10 surface but fails to enter. In the present study, we focus on characterizing ND10-ES. Here we report the following. (i) Fusion of ICP0 with ND10 relies on specific sequences located within ND10-ES. Replacement of ND10-ES by the corresponding region from ORF61 of varicella-zoster virus did not rescue ND10 fusion. (ii) Three tandem ND10 fusion segments (ND10-FS1, ND10-FS2, and ND10-FS3), encompassing 200 amino acids within ND10-ES, redundantly facilitate fusion. Each of the three segments is sufficient to independently drive the fusion process, but none of the segments by themselves are necessary for ND10 fusion. Only when all three segments are deleted is fusion blocked. (iii) The SUMO interaction motif located within ND10-FS2 is not required for ND10 fusion but is required for the complete degradation of PML, suggesting that PML degradation and ND10 fusion are regulated by different molecular mechanisms.ImportanceND10 nuclear bodies are part of the cell-intrinsic antiviral defenses that restrict viral gene expression upon virus infection. As a countermeasure, infected cell protein 0 (ICP0) of herpes simplex virus 1 (HSV-1) localizes to ND10s, degrades the ND10 organizer, and disperses ND10 components in order to alleviate repression. We studied the ICP0-ND10 association to delineate elements important for this dynamic interaction and to understand its role in viral replication and host defense. In this work, we show that ICP0 contains three redundant segments to ensure an effective mergence of ICP0 with ND10 nuclear bodies. This is the first study to systematically investigate ICP0 elements that are important for ICP0-ND10 fusion.

Dataset Information

Role of nuclear factor Y in stress-induced activation of the herpes simplex virus type 1 ICP0 promoter.

Publications

Role of nuclear factor Y in stress-induced activation of the herpes simplex virus type 1 ICP0 promoter.

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