The prototype γ-2 herpesvirus nucleocytoplasmic shuttling protein, ORF 57, transports viral RNA through the cellular mRNA export pathway

Williams, Ben J. L.; Boyne, James R.; Goodwin, Delyth J.; Roaden, Louise; Hautbergue, Guillaume M.; Wilson, Stuart A.; Whitehouse, Adrian

doi:10.1042/bj20041223

Cited by 68 publications

(98 citation statements)

References 51 publications

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“…Instead, we observed higher levels of gH and gL total RNA, which seemed to be contributed from both nucleus and cytoplasm proportionally in the presence of ORF57. The preferential accumulation of target RNA in the cytoplasm has been used to support a role for some ORF57s in the egress of RNA from the nucleus (4,6,29,41). In our study, the overall increase of total RNA levels of the target gene was contributed by nuclear and cytoplasmic compartments (Fig.…”

Section: Discussionsupporting

confidence: 65%

“…However, as the name MTA (mRNA transcript accumulation) in KSHV implies, a posttranscriptional mechanism of activation by ORF57 orthologues has been studied and documented most extensively (4,14,21,29). It has been reported that increased expression appears to be achieved in many cases via the facilitation of the nuclear export of target mRNAs (4,6,8,29,41). Many herpesviral mRNAs, most of which are intronless and therefore do not undergo splicing, seem to be poor substrates for nuclear export by the regular cellular transport machineries.…”

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confidence: 99%

“…Many herpesviral mRNAs, most of which are intronless and therefore do not undergo splicing, seem to be poor substrates for nuclear export by the regular cellular transport machineries. The facilitation of nuclear export may be achieved at least in part by the subversion of cellular RNA export machineries for the efficient expression of viral genes (8,17,21,41). ORF57 binds to RNA export factor (REF; also known as ALY), which is one component of the transcription export (TREX) complex.…”

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confidence: 99%

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Rhesus Monkey Rhadinovirus ORF57 Induces gH and gL Glycoprotein Expression through Posttranscriptional Accumulation of Target mRNAs

Shin

Desrosiers

2011

J Virol

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Open reading frame 57 (ORF57) of gamma-2 herpesviruses is a key regulator of viral gene expression. It has been reported to enhance the expression of viral genes by transcriptional, posttranscriptional, or translational activation mechanisms. Previously we have shown that the expression of gH and gL of rhesus monkey rhadinovirus (RRV), a close relative of the human Kaposi's sarcoma-associated herpesvirus (KSHV), could be dramatically rescued by codon optimization as well as by ORF57 coexpression (J. P. Bilello, J. S. Morgan, and R. C. Desrosiers, J. Virol. 82:7231-7237, 2008). We show here that ORF57 coexpression and codon optimization had similar effects, except that the rescue of expression by codon optimization was temporally delayed relative to that of ORF57 coexpression. The transfection of gL mRNA directly into cells with or without ORF57 coexpression and with or without codon optimization recapitulated the effects of these modes of induction on transfected DNA. These findings suggested an important role for the enhancement of mRNA stability and/or the translation of mRNA for these very different modes of induced expression. This conclusion was confirmed by several different measures of gH and gL mRNA stability and accumulation with or without ORF57 coexpression and with or without codon optimization. Our results indicate that RRV gH and gL expression is severely limited by the stability of the mRNA and that ORF57 coexpression and codon optimization independently induce gH and gL expression principally by allowing accumulation and translation of these mRNAs.

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Section: Discussionsupporting

confidence: 65%

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confidence: 99%

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confidence: 99%

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Rhesus Monkey Rhadinovirus ORF57 Induces gH and gL Glycoprotein Expression through Posttranscriptional Accumulation of Target mRNAs

Shin

Desrosiers

2011

J Virol

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“…The nucleolus is necessary for protein translation {reviewed in (Melese and Xue, 1995;Pederson and Politz, 2000)}. It has been proposed that the herpesvirus saimiri ORF57 protein uses nucleoli to export intronless viral messages (Boyne and Whitehouse, 2006;Williams et al, 2005). The HSV-1 ICP27, ICP0, γ 1 34.5, and U S 11 proteins were reported to possess nucleolar targeting sequences (Cheng et al, 2002;MacLean et al, 1987;Mears et al, 1995;Morency et al, 2005) but the implications of these are unknown.…”

Section: Vp22 Targets Nucleolinmentioning

confidence: 99%

The major tegument structural protein VP22 targets areas of dispersed nucleolin and marginalized chromatin during productive herpes simplex virus 1 infection

et al. 2008

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The HSV major tegument structural protein VP22 resides in multiple subcellular regions during productive infection. During an analysis of the molecular determinants of these localizations, we observed that a transfected fusion of the C-terminal portion of VP22, containing its pat4 nuclear localization signal, with GFP lacked nucleolar sparing compared to GFP alone. Thus, the initial goal was to determine whetherr VP22 associates with nucleoli. Using an optimized indirect immunofluorescence system to visualize nucleolin and viral proteins, we observed that VP22 present in VP22-expressing Vero (V49) cells "surrounded" nucleolin. These two initial findings implied that VP22 might associate directly with nucleoli. We next analyzed HSV infected cells and observed that at late times, anti-nucleolin immune reactivity was dispersed throughout the nuclei while it retained uniform, circular staining in mock-infected cells. Time course infection experiments indicated that nucleolin initiated its transition from uniform to dispersed structures between 2 and 4 hpi. Comparison of Hoechst stained nuclei showed bright anti-nucleolin staining localized to regions of marginalized chromatin. These effects required de novo infected cell protein synthesis. A portion of VP22 detected in nuclei at 4 and 6 hpi localized to these areas of altered nucleolin and marginalized chromatin. VP22 was excluded from viral replication compartments containing the viral regulatory protein ICP22. Finally, altered nucleolin and marginalized chromatin were detected with a VP22-null virus, indicating that VP22 was not responsible for these nuclear architecture alterations. Thus, we conclude that nuclear VP22 targets unique subnuclear structures early (< 6 hpi) during HSV-1 infection.

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“…Further analysis has demonstrated that the ORF57 protein has the ability to bind viral RNA and shuttle between the nucleus and cytoplasm and is required for efficient cytoplasmic accumulation of virus mRNA (15). More recently, we have shown that ORF57 interacts with two distinct cellular pathways involved in cellular nuclear import and export (16,17). We have demonstrated that the ORF57 protein interacts with importin-␣ through a classical nuclear localization signal (NLS) within ORF57, allowing it to shuttle into the nucleus (16).…”

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confidence: 99%

Nucleolar trafficking is essential for nuclear export of intronless herpesvirus mRNA

Boyne

Whitehouse

2006

Proc. Natl. Acad. Sci. U.S.A.

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The nucleolus is the largest subnuclear structure and is plurifunctional in nature. Here, we demonstrate that nucleolar localization of a key herpesvirus regulatory protein is essential for its role in virus mRNA nuclear export. The herpesvirus saimiri ORF57 protein is a nucleocytoplasmic shuttle protein that is conserved in all herpesviruses and orchestrates the nuclear export of viral intronless mRNAs. We demonstrate that expression of the ORF57 protein induces nucleolar redistribution of human TREX (transcription͞ export) proteins that are involved in mRNA nuclear export. Moreover, we describe a previously unidentified nucleolar localization signal within ORF57 that is composed of two distinct nuclear localization signals. Intriguingly, point mutations that ablate ORF57 nucleolar localization lead to a failure of ORF57-mediated viral mRNA nuclear export. Furthermore, nucleolar retargeting of the ORF57 mutant was achieved by the incorporation of the HIV-1 Rev nucleolar localization signal, and analysis demonstrated that this modification was sufficient to restore viral mRNA nuclear export. This finding represents a unique and fundamental role for the nucleolus in nuclear export of viral mRNA.mRNA export ͉ nucleolus ͉ virus T he eukaryotic cell nucleus is a highly organized environment containing distinct and often dynamic compartments (1). Of these, the nucleolus is the most prominent, and, for many years, its exclusive role was thought to be the site of ribosomal RNA transcription, processing, and assembly into the ribosome subunits (2). Recent studies, however, suggest that it has additional nonclassical roles in many aspects of cell biology, including cell cycle regulation, viral replication, tumorigenesis, and cellular stress responses (3-5). This plurifunctional nature of the nucleolus has been highlighted by extensive proteomic analysis of human nucleoli (6, 7). To date, the nucleolar proteome database archives 728 nucleolar proteins, and functional classification of these proteins reinforces the multiple roles of the nucleolus (8). Furthermore, there is constant dynamic trafficking of nucleolar proteins, and this concomitant dynamic nature of nucleolar structure may provide regulation of nonclassical nucleolar functions.Interestingly, an increasing number of key proteins from both RNA and DNA viruses have been shown to localize to the nucleolus. These proteins include those encoded by viruses such as coronaviruses, influenza, HIV-1, adenoviruses, and herpesviruses (9). Therefore, virus-nucleolar interactions are likely to have important implications in the life cycle of many viruses. However, at present, the precise functional role of these virus-nucleolar colocalizations has not been determined. One such key viral protein that traffics to the nucleolus is the herpesvirus saimiri (HVS) ORF57 protein. HVS is the prototype ␥-2 herpesvirus, or rhadinovirus (10), which has become an important family of viruses since the identification of the first human ␥-2 herpesvirus, the oncogenic Kaposi's sarcoma-associ...

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The prototype γ-2 herpesvirus nucleocytoplasmic shuttling protein, ORF 57, transports viral RNA through the cellular mRNA export pathway

Cited by 68 publications

References 51 publications

Rhesus Monkey Rhadinovirus ORF57 Induces gH and gL Glycoprotein Expression through Posttranscriptional Accumulation of Target mRNAs

Rhesus Monkey Rhadinovirus ORF57 Induces gH and gL Glycoprotein Expression through Posttranscriptional Accumulation of Target mRNAs

The major tegument structural protein VP22 targets areas of dispersed nucleolin and marginalized chromatin during productive herpes simplex virus 1 infection

Nucleolar trafficking is essential for nuclear export of intronless herpesvirus mRNA

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