Direct Stimulation of Translation by the Multifunctional Herpesvirus ICP27 Protein

Larralde, Osmany; Smith, Richard; Wilkie, Gavin S.; Malik, Poonam; Gray, Nicola K.; Clements, J. Barklie

doi:10.1128/jvi.80.3.1588-1591.2006

Cited by 49 publications

(56 citation statements)

References 42 publications

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“…Consistent with its role as an mRNA-specific translational activator (7,8,14), ICP27 binds RNA, cosediments with polyribosomes (14), and can be isolated with components of the translational machinery (10,15). Because ICP27 can stimulate translation in the absence of other viral proteins when tethered to the 3′ UTR of reporter mRNAs (14), its interaction with the translational machinery must either be direct or mediated indirectly by other cellular proteins, further supporting the idea that it may share a mechanism of action with cellular regulators of translation.…”

Section: Significancementioning

confidence: 71%

“…Because ICP27 can stimulate translation in the absence of other viral proteins when tethered to the 3′ UTR of reporter mRNAs (14), its interaction with the translational machinery must either be direct or mediated indirectly by other cellular proteins, further supporting the idea that it may share a mechanism of action with cellular regulators of translation. Here, we investigate its mechanism of action, establishing that it requires recruitment of PABP, via a direct protein interaction, to ICP27-bound mRNAs.…”

Section: Significancementioning

confidence: 96%

See 1 more Smart Citation

Viral and cellular mRNA-specific activators harness PABP and eIF4G to promote translation initiation downstream of cap binding

Smith

Anderson

Larralde

et al. 2017

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

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Regulation of mRNA translation is a major control point for gene expression and is critical for life. Of central importance is the complex between cap-bound eukaryotic initiation factor 4E (eIF4E), eIF4G, and poly(A) tail-binding protein (PABP) that circularizes mRNAs, promoting translation and stability. This complex is often targeted to regulate overall translation rates, and also by mRNA-specific translational repressors. However, the mechanisms of mRNA-specific translational activation by RNA-binding proteins remain poorly understood. Here, we address this deficit, focusing on a herpes simplex virus-1 protein, ICP27. We reveal a direct interaction with PABP that is sufficient to promote PABP recruitment and necessary for ICP27-mediated activation. PABP binds several translation factors but is primarily considered to activate translation initiation as part of the PABP-eIF4G-eIF4E complex that stimulates the initial cap-binding step. Importantly, we find that ICP27-PABP forms a complex with, and requires the activity of, eIF4G. Surprisingly, ICP27-PABP-eIF4G complexes act independently of the effects of PABP-eIF4G on cap binding to promote small ribosomal subunit recruitment. Moreover, we find that a cellular mRNA-specific regulator, Deleted in Azoospermia-like (Dazl), also employs the PABP-eIF4G interaction in a similar manner. We propose a mechanism whereby diverse RNA-binding proteins directly recruit PABP, in a non-poly(A) tail-dependent manner, to stimulate the small subunit recruitment step. This strategy may be particularly relevant to biological conditions associated with hypoadenylated mRNAs (e.g., germ cells/neurons) and/or limiting cytoplasmic PABP (e.g., viral infection, cell stress). This mechanism adds significant insight into our knowledge of mRNA-specific translational activation and the function of the PABP-eIF4G complex in translation initiation.D espite the importance of translational control, the mechanisms by which specific subsets of mRNAs are translationally regulated are only well defined in a handful of cases. Nevertheless, it is clear that regulation is most often mediated by factors recruited to the 3′ untranslated region (UTR) of mRNAs and frequently occurs at the level of initiation (1). Initiation is a multistep process involving several mRNA-dependent steps, each of which requires eukaryotic initiation factors (eIFs) (2). Initially, the m 7 GpppX cap is bound by eIF4F, comprising a large scaffold protein, eIF4G, bound to the cap-binding protein, eIF4E, and an RNA helicase, eIF4A. The small (40S) ribosomal subunit, initiator tRNA, and associated initiation factors are then recruited as a 43S preinitiation complex. Recruitment is facilitated by eIF4A-dependent removal of RNA secondary structure and by the interaction of 40S-associated eIF3 with eIF4G. The 43S small ribosomal subunit complex then scans the 5′ UTR to locate a start codon, recognition of which promotes release of initiation factors and joining of the large (60S) ribosomal subunit to form an 80S ribosome. Like the cap,...

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Section: Significancementioning

confidence: 71%

Section: Significancementioning

confidence: 96%

Viral and cellular mRNA-specific activators harness PABP and eIF4G to promote translation initiation downstream of cap binding

Smith

Anderson

Larralde

et al. 2017

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

Self Cite

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“…Given that each mRNA was synthesized in vitro and transfected directly into cells in this assay, it is not likely that any events related to nuclear export processes were involved. The increased levels of translation could result from the direct activation of translation by ORF57 (5,13,22) or from the increased stabilization of the RNA by ORF57 (see below). Increasing levels of ORF57 protein expression were achieved from increasing inputs of ORF57 plasmid DNA.…”

Section: Resultsmentioning

confidence: 99%

“…In a tethered function assay of Xenopus oocytes, herpes simplex virus (HSV) ICP27 has been shown to activate translation (22). Also, KSHV ORF57 activated the translation of intronless mRNAs through direct interaction with PYM, subsequently recruiting 48S preinitiation complex onto newly exported mRNAs (5).…”

mentioning

confidence: 99%

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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“…Our attention was drawn to the predicted interaction of pUL69 with poly(A)-binding protein C1 (PABPC1) and eukaryotic initiation factor 4A1 (eIF4A1), because the HSV pUL69 homolog, ICP27, has been shown to interact with initiation factors, including PABP (20), and facilitate the translation of a subset of virus-coded mRNAs (21)(22)(23). PABPC1 and eIF4A1 are both constituents of the mRNA cap-binding complex, raising the possibility that pUL69 interacts with them to modulate translation.…”

Section: Hcmv-coded Pul69 Interacts With Eif4a1 and Poly(a)-bindingmentioning

confidence: 99%

Human cytomegalovirus UL69 protein facilitates translation by associating with the mRNA cap-binding complex and excluding 4EBP1

Aoyagi

Gaspar

Shenk

2010

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

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4EBP1 is phosphorylated by the mTORC1 kinase. When mTORC1 activity is inhibited, hypophosphorylated 4EBP1 binds and sequesters eIF4E, a component of the mRNA cap-binding complex, and blocks translation. As a consequence, mTORC1 activity is needed to maintain active translation. The human cytomegalovirus pUL38 protein preserves mTORC1 activity, keeping most of the E4BP1 in the infected cell in a hyperphosphorylated, inactive state. Here we report that a second viral protein, pUL69, also antagonizes the activity of 4EBP1, but by a separate mechanism. pUL69 interacts directly with eIF4A1, an element of the cap-binding complex, and the poly(A)-binding protein, which binds to the complex. When pUL69 accumulates during infection with wild-type virus, 4EBP1 is excluded from the complex. However, 4EBP1 is present in the cap-binding complex after infection with a pUL69-deficient virus, coincident with reduced accumulation of several late virus-coded proteins. We propose that pUL69 supports translation in human cytomegalovirus-infected cells by excluding hypophosphorylated 4EBP1 from the cap-binding complex.translational control | two-hybrid screen | eukaryotic initiation factor 4A

show abstract

Direct Stimulation of Translation by the Multifunctional Herpesvirus ICP27 Protein

Cited by 49 publications

References 42 publications

Viral and cellular mRNA-specific activators harness PABP and eIF4G to promote translation initiation downstream of cap binding

Viral and cellular mRNA-specific activators harness PABP and eIF4G to promote translation initiation downstream of cap binding

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

Human cytomegalovirus UL69 protein facilitates translation by associating with the mRNA cap-binding complex and excluding 4EBP1

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