The Ref/Aly proteins are dispensable for mRNA export and development in <i>Caenorhabditis elegans</i>

Longman, Dáša; Johnstone, Iain L.; Cáceres, Javier F.

doi:10.1261/rna.5420503

Cited by 94 publications

(92 citation statements)

References 77 publications

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“…This conclusion was further supported by the observation that cells with a knockdown of REF expression had no defect in ORF57-enhanced ORF59 expression. Other studies also show no defect in RNA export in REF knock-out animals (34,51). During the course of our manuscript preparation, Chen et al (52) reported that HSV-1 ICP27, a hom- olog of KSHV ORF57, mediates viral RNA export through the TAP/NXF1 pathway independent of its interaction with REF.…”

Section: Discussionmentioning

confidence: 64%

Structural and Functional Analyses of Kaposi Sarcoma-associated Herpesvirus ORF57 Nuclear Localization Signals in Living Cells

Majerčiak

Yamanegi

Nie

et al. 2006

Journal of Biological Chemistry

206

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Kaposi sarcoma-associated herpesvirus (KSHV) ORF57 is a multifunctional, nuclear protein involved in post-transcriptional regulation of a subset of viral genes during lytic replication. Three nuclear localization signals (NLSs), NLS1 (amino acids (aa 101-107), NLS2 (aa 121-130), and NLS3 (aa 143-152), were identified in the N terminus of the ORF57 protein, and each of the three represents a short stretch of basic amino acid residues. Disruption of all three NLSs prevented localization of ORF57 in the nucleus. Insertion of individual NLSs into a heterologous cytoplasmic protein converted it into a nuclear protein, confirming that each NLS functions independently and is sufficient to promote protein nuclear localization. Although it exhibits a function similar to that of Epstein-Barr virus EB2 in promoting KSHV ORF59 expression, KSHV ORF57 differs from the herpes simplex virus ICP27 protein, and its function could be disrupted by point mutations of single or two NLSs in random combination, despite the proper localization of the mutant protein in the nucleus. The dysfunctional ORF57 containing NLS mutations also had low affinity with ORF59 RNA and the RNA export factor REF. However, the REF binding of ORF57 in vivo appeared to have no effect on ORF57-mediated enhancement of ORF59 expression. Thus, the three NLSs identified in ORF57 provide at least two functions, nuclear localization of ORF57 and up-regulation of ORF59 expression.

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Section: Discussionmentioning

confidence: 64%

Structural and Functional Analyses of Kaposi Sarcoma-associated Herpesvirus ORF57 Nuclear Localization Signals in Living Cells

Majerčiak

Yamanegi

Nie

et al. 2006

Journal of Biological Chemistry

206

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“…In contrast, TAP-mediated export of cellular poly(A) + mRNAs involves its indirect recruitment to mRNAs by mRNA export adapter proteins such as Aly/REF (Yra1p in yeast) Stutz et al 2000;Zhou et al 2000;Rodrigues et al 2001). Given that Aly/REF is not essential for mRNA export (Gatfield and Izaurralde 2002;Longman et al 2003) and that other RNA binding proteins have been shown to interact with TAP (Huang et al 2003), it is likely that Aly/REF is only one of a number of adapter proteins for TAP.…”

Section: Introductionmentioning

confidence: 99%

Nuclear export of metazoan replication-dependent histone mRNAs is dependent on RNA length and is mediated by TAP

Erkmann

Sánchez²,

Treichel

et al. 2004

RNA

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Replication-dependent histone mRNAs are the only metazoan mRNAs that are not polyadenylated, ending instead in a conserved stem-loop sequence. Histone pre-mRNAs lack introns and are processed in the nucleus by a single cleavage step, which produces the mature 3 end of the mRNA. We have systematically examined the requirements for the nuclear export of a mouse histone mRNA using the Xenopus oocyte system. Histone mRNAs were efficiently exported when injected as mature mRNAs, demonstrating that the process of 3 end cleavage is not required for export factor binding. Export also does not depend on the stem-loop binding protein (SLBP) since mutations of the stem-loop that prevent SLBP binding and competition with a stem-loop RNA did not affect export. Only the length of the region upstream of the stem-loop, but not its sequence, was important for efficient export. Histone mRNA export was blocked by competition with constitutive transport element (CTE) RNA, indicating that the mRNA export receptor TAP is involved in histone mRNA export. Consistent with this observation, depletion of TAP from Drosophila cells by RNAi resulted in the restriction of mature histone mRNAs to the nucleus.

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“…Thus, it has a role in DNA replication distinct from its role in mRNA export (24). Although Aly directly binds UAP56 and couples it to spliced mRNA, REF/Aly is dispensable for mRNA export in Drosophila (25) and Caenorhabditis elegans (26).…”

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confidence: 99%

Akt phosphorylation and nuclear phosphoinositide association mediate mRNA export and cell proliferation activities by ALY

Okada

Jang

2008

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

103

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Nuclear PI3K and its downstream effectors play essential roles in a variety of cellular activities including cell proliferation, survival, differentiation, and pre-mRNA splicing. Aly is a nuclear speckle protein implicated in mRNA export. Here we show that Aly is a physiological target of nuclear PI3K signaling, which regulates its subnuclear residency, cell proliferation, and mRNA export activities through nuclear Akt phosphorylation and phosphoinositide association. Nuclear Akt phosphorylates Aly on threonine-219, which is required for its interaction with Akt. Aly binds phosphoinositides, and this action is regulated by Akt-mediated phosphorylation. Phosphoinositide binding but not Akt phosphorylation dictates Aly's nuclear speckle residency. Depletion of Aly results in cell growth suppression and mRNA export reduction. Inhibition of Aly phosphorylation substantially decreases cell proliferation and mRNA export. Furthermore, disruption of phosphoinositide association with Aly also significantly reduces these activities. Thus, nuclear PI3K signaling mediates both cell proliferation and mRNA export functions of Aly.nuclear PI 3-kinase ͉ nuclear speckle ͉ nuclear Akt ͉ T219 phosphorylation P I3K and Akt predominantly locate in the cytoplasm, but they also occur in the nucleus or translocate there upon stimulation. Most of phosphoinositol lipid metabolic enzymes and PI3K signaling machinery occur in the nucleus. For example, PI-PLC (1, 2), phosphatidylinositol phosphate kinases (3, 4), PDK1 (5), PTEN (6 -8), and Akt (9, 10). Nuclear phosphoinositides play critical roles in cell growth and differentiation (11). In addition to nuclear membrane, phosphoinositides also associate with the nuclear speckles, a peculiar nuclear subcompartment enriched in small ribonucleoprotein (RNP) particles and various splicing factors (12), where many elements of nuclear phosphoinositide metabolism, including PI(4,5)P 2 , are concentrated (4,13,14). Nuclear phosphoinositides may be implicated in pre-mRNA splicing and chromatin structure (11). It has been shown before that nuclear PI(4,5)P 2 assembles in a mitotically regulated particle involved in pre-mRNA splicing (14). Elements of the transcriptional and pre-mRNA processing machinery interact with this pool of nuclear PI(4,5)P 2 , and PI(4,5)P 2 immunoprecipitates contain intermediates and products of the splicing reaction. Alternative splicing of pre-mRNAs can be regulated by extracellular signals such as growth factors, cytokines, hormones, and stress stimuli (15). For instance, insulin-activated PI3K signaling has been shown to implicate in mammary epithelial-mesenchymal interaction, which regulates fibronectin alternative splicing (16).Splicing of pre-mRNA and export of mRNA are normally coupled (17-19). Pre-mRNA splicing has been proposed to stimulate mRNA export (17,20). Based on genetic and biochemical evidence, Reed et al. (21) proposed a model for mRNA export: nascent pre-mRNA is first packaged into heterogeneous nuclear RNP (hnRNP) particles. During spliceosome assembly,...

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The Ref/Aly proteins are dispensable for mRNA export and development in Caenorhabditis elegans

Abstract: The mRNA export pathway is highly conserved throughout evolution. We have used RNA interference (RNAi) to functionally characterize bona fide RNA export factors and components of the exon-exon junction complex (EJC) in Caenorhabditis elegans. RNAi of

Cited by 94 publications

References 77 publications

Structural and Functional Analyses of Kaposi Sarcoma-associated Herpesvirus ORF57 Nuclear Localization Signals in Living Cells

Structural and Functional Analyses of Kaposi Sarcoma-associated Herpesvirus ORF57 Nuclear Localization Signals in Living Cells

Nuclear export of metazoan replication-dependent histone mRNAs is dependent on RNA length and is mediated by TAP

Akt phosphorylation and nuclear phosphoinositide association mediate mRNA export and cell proliferation activities by ALY

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