Nucleolar disruption impairs Kaposi's sarcoma‐associated herpesvirus ORF57‐mediated nuclear export of intronless viral mRNAs

Boyne, James R.; Whitehouse, Adrian

doi:10.1016/j.febslet.2009.10.040

Cited by 30 publications

(40 citation statements)

References 37 publications

(57 reference statements)

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“…Although an effect on export has been suggested based on reports of increased cytoplasmic accumulation of some KSHV mRNAs in the presence of ORF57, such findings have not been universally replicated (4,6,36). In order to compare the cytoplasmic accumulation of representative KSHV mRNAs in the presence of ORF57Pmut and wtORF57, we separated and measured cytoplasmic and nuclear RNA from cells expressing specific KSHV target mRNAs and either wtORF57 or ORF57Pmut.…”

Section: Resultsmentioning

confidence: 99%

Binding of Cellular Export Factor REF/Aly by Kaposi's Sarcoma-Associated Herpesvirus (KSHV) ORF57 Protein Is Not Required for Efficient KSHV Lytic Replication

Verma²,

Swaminathan

2012

J Virol

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Kaposi's sarcoma-associated herpesvirus (KSHV) ORF57 protein is expressed early during lytic KSHV replication, enhances expression of many KSHV genes, and is essential for virus production. ORF57 is a member of a family of proteins conserved among all human and many animal herpesviruses that are multifunctional regulators of gene expression and act posttranscriptionally to increase accumulation of their target mRNAs. The mechanism of ORF57 action is complex and may involve effects on mRNA transcription, stability, and export. ORF57 directly binds to REF/Aly, a cellular RNA-binding protein component of the TREX complex that mediates RNA transcription and export. We analyzed the effects of an ORF57 mutation known to abrogate REF/Aly binding and demonstrate that the REF-binding mutant is impaired in activation of viral mRNAs and noncoding RNAs confined to the nucleus. Although the inability to bind REF leads to decreased ORF57 activity in enhancing gene expression, there is no demonstrable effect on nuclear export of viral mRNA or the ability of ORF57 to support KSHV replication and virus production. These data indicate that REF/Aly-ORF57 interaction is not essential for KSHV lytic replication but may contribute to target RNA stability independent of effects on RNA export, suggesting a novel role for REF/Aly in viral RNA metabolism.

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Section: Resultsmentioning

confidence: 99%

Binding of Cellular Export Factor REF/Aly by Kaposi's Sarcoma-Associated Herpesvirus (KSHV) ORF57 Protein Is Not Required for Efficient KSHV Lytic Replication

Verma²,

Swaminathan

2012

J Virol

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“…To this end, KSHV ORF57 binds viral intronless mRNAs, shuttles between the nucleus, nucleolus, and the cytoplasm, and mediates the nuclear export of intronless viral mRNAs via a TAP-mediated pathway (3,5,7). These properties are also conserved in ORF57 homologues throughout herpesviruses such as ICP27 from herpes simplex virus type 1 (HSV-1) (12,13,28,43), SM protein from Epstein-Barr virus (EBV) (41,45), and herpesvirus saimiri (HVS) ORF57 protein (2,8,14,15,22).…”

mentioning

confidence: 98%

“…After 24 h, RNA was extracted from total and cytoplasmic fractions, and the RNA levels were assessed using quantitative RT-PCR as previously described (7). The total RNA levels were assessed to ensure similar expression levels of the ORF47 mRNA.…”

Section: Vol 85 2011 C-terminal Mutation Of Kshv Orf57 Affects Its mentioning

confidence: 99%

“…ORF57 also contains two separate arginine-glycine-glycine (RGG) motifs, similar to an RGG box motif, responsible for RNA binding in HSV ICP27 (36). Nuclear targeting is mediated by three functionally independent nuclear localization signals (NLS) (34), and NLS2 or NLS3 in combination with NLS1 are able to function as a nucleolar targeting signal (7). The carboxy-terminal contains a potential leucine zipper motif, a zinc finger-like motif.…”

mentioning

confidence: 99%

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Mutation of a C-Terminal Motif Affects Kaposi's Sarcoma-Associated Herpesvirus ORF57 RNA Binding, Nuclear Trafficking, and Multimerization

Taylor

Jackson

Noerenberg

et al. 2011

J Virol

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The Kaposi's sarcoma-associated herpesvirus (KSHV) ORF57 protein is essential for virus lytic replication. ORF57 regulates virus gene expression at multiple levels, enhancing transcription, stability, nuclear export, and translation of viral transcripts. To enhance the nuclear export of viral intronless transcripts, ORF57 (i) binds viral intronless mRNAs, (ii) shuttles between the nucleus, nucleolus, and the cytoplasm, and (iii) interacts with multiple cellular nuclear export proteins to access the TAP-mediated nuclear export pathway. We investigated the implications on the subcellular trafficking, cellular nuclear export factor recruitment, and ultimately nuclear mRNA export of an ORF57 protein unable to bind RNA. We observed that mutation of a carboxy-terminal RGG motif, which prevents RNA binding, affects the subcellular localization and nuclear trafficking of the ORF57 protein, suggesting that it forms subnuclear aggregates. Further analysis of the mutant shows that although it still retains the ability to interact with cellular nuclear export proteins, it is unable to export viral intronless mRNAs from the nucleus. Moreover, computational molecular modeling and biochemical studies suggest that, unlike the wild-type protein, this mutant is unable to self-associate. Therefore, these results suggest the mutation of a carboxy-terminal RGG motif affects ORF57 RNA binding, nuclear trafficking, and multimerization.

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“…However, much remains to be understood. We are currently investigating what role nucleolar shuttling of ORF57 plays in KSHV mRNA biogenesis 11 and attempting to delineate the regulatory networks that must modulate ORF57 in order to allow such a diverse set of functions to be performed by a single virus protein.…”

Section: Orf57mentioning

confidence: 99%

ORF57: Master regulator of KSHV mRNA biogenesis

2010

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Nucleolar disruption impairs Kaposi's sarcoma‐associated herpesvirus ORF57‐mediated nuclear export of intronless viral mRNAs

Cited by 30 publications

References 37 publications

Binding of Cellular Export Factor REF/Aly by Kaposi's Sarcoma-Associated Herpesvirus (KSHV) ORF57 Protein Is Not Required for Efficient KSHV Lytic Replication

Binding of Cellular Export Factor REF/Aly by Kaposi's Sarcoma-Associated Herpesvirus (KSHV) ORF57 Protein Is Not Required for Efficient KSHV Lytic Replication

Mutation of a C-Terminal Motif Affects Kaposi's Sarcoma-Associated Herpesvirus ORF57 RNA Binding, Nuclear Trafficking, and Multimerization

ORF57: Master regulator of KSHV mRNA biogenesis

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