Regulation of mRNA export in response to stress in Saccharomyces cerevisiae.

Saavedra, Claudio A.; Tung, Kuei-Shu; Amberg, David C.; Hopper, Anita K.; Cole, Charles N.

doi:10.1101/gad.10.13.1608

Cited by 166 publications

(206 citation statements)

References 68 publications

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“…This opens the possibility that, in vivo, the ATPase activity of Dbp5 could be modulated to regulate mRNA export. For example, it has been reported that during heat shock, bulk mRNA export is blocked and polyadenylated RNA accumulates inside the nucleus (39). Whether this is the result of decreased Dbp5 ATPase activity is unknown, but potential regulation of Dbp5 could occur through the modulation of InsP 6 levels or availability.…”

Section: Discussionmentioning

confidence: 99%

Structure of the C-terminus of the mRNA export factor Dbp5 reveals the interaction surface for the ATPase activator Gle1

Dossani

Weirich

Erzberger

et al. 2009

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

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The DExD/H-box RNA-dependent ATPase Dbp5 plays an essential role in the nuclear export of mRNA. Dbp5 localizes to the nuclear pore complex, where its ATPase activity is stimulated by Gle1 and its coactivator inositol hexakisphosphate. Here, we present the crystal structure of the C-terminal domain of Dbp5, refined to 1.8 Å. The structure reveals a RecA-like fold that contains two defining characteristics not present in other structurally characterized DExD/H-box proteins: a C-terminal ␣-helix and a loop connecting ␤5 and ␣4, both of which are composed of conserved and unique elements in the Dbp5 primary sequence. Using structure-guided mutagenesis, we have identified several charged surface residues that, when mutated, weaken the binding of Gle1 and inhibit the ability of Gle1 to stimulate Dbp5's ATPase activity. In vivo analysis of the same mutations reveals that those mutants displaying the weakest ATPase stimulation in vitro are also unable to support yeast growth. Analysis of the correlation between the in vitro and in vivo data indicates that a threshold level of Dbp5 ATPase activity is required for cellular mRNA export that is not met by the unstimulated enzyme, suggesting a possible mechanism by which Dbp5's activity can be modulated to regulate mRNA export. crystal structure ͉ DExD/H-box ͉ nuclear pore complex N uclear mRNA export is an essential yet poorly understood step in the expression of all protein-encoding nuclear genes. mRNAs are synthesized in the nucleus, where they associate with several proteins into mRNA-protein complexes (mRNPs). mRNP composition changes during the process of mRNA maturation, which involves a number of modifications, including capping, splicing, and polyadenylation (1). All these processes seem to be interconnected to provide a mechanism by which only fully and correctly processed transcripts are competent for export to the cytoplasm and gain access to the translational machinery (2). mRNP export depends on the essential export receptor, a heterodimer of Mex67/Mtr2 (TAP/p15 in metazoans), which facilitates the passage of mRNAs through nuclear pore complexes (NPCs) by interacting with specific NPC components (3-5). Immunoelectron microscopy studies have revealed that mRNPs are remodeled during NPC engagement and export, with specific proteins dissociating from the mRNP at distinct stages of export (6). Proper remodeling during export is likely to be essential for providing directionality to the mRNA export process.The conserved DExD/H-box protein Dbp5 is enriched at the cytoplasmic face of the NPC and has been suggested to play a critical role in the mRNP rearrangement observed on cytoplasmic entry (7-10). Members of the DExD/H-box protein family are required for all aspects of RNA processing and are thought to couple the energy of ATP hydrolysis to drive the remodeling of RNA molecules (11). DExD/H-box proteins possess several distinct biochemical activities in vitro, including double-stranded RNA duplex unwinding and the removal of RNA-associated proteins (12-15). However...

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Section: Discussionmentioning

confidence: 99%

Structure of the C-terminus of the mRNA export factor Dbp5 reveals the interaction surface for the ATPase activator Gle1

Dossani

Weirich

Erzberger

et al. 2009

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

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“…In addition to the repression of pre-mRNA splicing, exposure to severe heat shock stress at 42°C causes inhibition of mRNA export from the nucleus to the cytoplasm, which leads to accumulation of bulk poly (A) + RNA in the nuclei (Tani et al, 1995;Saavedra et al, 1996;Liu et al, 1996). Interestingly, it was shown that heat-shock inducible SSA1 and SSA4 mRNAs encoding heat shock proteins are exported to the cytoplasm under the same stressed conditions, indicating the presence of selective export pathways for heat shock mRNAs (Saavedra et al, 1996;Liu et al, 1996;Saavedra et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

“…Interestingly, it was shown that heat-shock inducible SSA1 and SSA4 mRNAs encoding heat shock proteins are exported to the cytoplasm under the same stressed conditions, indicating the presence of selective export pathways for heat shock mRNAs (Saavedra et al, 1996;Liu et al, 1996;Saavedra et al, 1997). The precise mechanisms for selective export of heat shock mRNAs are mostly unknown.…”

Section: Introductionmentioning

confidence: 99%

Hsp16p Is Required for Thermotolerance in Nuclear mRNA Export in Fission Yeast Schizosaccharomyces pombe

Yoshida

Tani

2005

Cell Struct. Funct.

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ABSTRACT. Export of mRNA from the nucleus to the cytoplasm is one of the essential steps for eukaryotic gene expression. In the fission yeast Schizosaccharomyces pombe, heat shock stress at 42°C causes block of mRNA export from the nucleus. We now report that saline and ethanol stresses also inhibit nuclear mRNA export, resulting in accumulation of bulk poly (A)+ RNA, as well as a specific mRNA, in the nucleus. Under stressed conditions, an mRNA export receptor Mex67p relocates to the nucleolus from the nuclear periphery and this relocation is closely correlated with inhibition of mRNA export by the stresses. Pretreatment of cells with a mild saline stress induced thermotolerance in mRNA export in a similar manner seen with mild heat pretreatment and protected mRNA export machinery from the subsequent severe heat shock. In contrast, mild ethanol stress could not induce the thermotolerance in mRNA export, suggesting that the stress response induced by ethanol differs from that induced by saline and heat shock stresses. In addition, we found that the Spc1p MAPK pathway is involved in induction of thermotolerance in mRNA export. Of the downstream targets for Spc1p, the Atf1p transcription factor was essential for induction of thermotolerance in mRNA export. We also found that Hsp16p, the expression of which is controlled by Atf1p, is involved in acquisition of thermotolerance in mRNA export in S. pombe.

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“…It appears to be mediated by nuclear export sequences present in RNA binding proteins such as HIV Rev (15). Poly(A) ϩ RNA export is dependent on the nucleotide state of Ran (10,16,17). Furthermore, binding of a heterodimeric protein complex is critical for export in the case of small nuclear RNAs, and this complex has recently been shown to interact with the ␣ subunit of importin (18,19).…”

mentioning

confidence: 99%

Importin/karyopherin protein family members required for mRNA export from the nucleus

Seedorf

Silver

1997

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

131

124

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The yeast Saccharomyces cerevisiae contains three proteins (Kap104p, Pse1p, and Kap123p) that share similarity to the 95-kDa ␤ subunit of the nuclear transport factor importin (also termed karyopherin and encoded by KAP95͞RSL1 in yeast). Proteins that contain nuclear localization sequences are recognized in the cytoplasm and delivered to the nucleus by the heterodimeric importin complex. A second importin-related protein, transportin, delivers a subset of heterogeneous nuclear ribonucleoproteins (hnRNPs) to the nucleoplasm. We now show that in contrast to loss of importin ␤ (Kap95p͞Rsl1p) and transportin (Kap104p), conditional loss of Pse1p in a strain lacking Kap123p results in a specific block of mRNA export from the nucleus. Overexpression of Sxm1p, a protein related to Cse1p in yeast and to the human cellular apoptosis susceptibility protein, relieves the defects of cells lacking Pse1p and Kap123p. Thus, a major role of Pse1p, Kap123p, and Sxm1p may be nuclear export rather than import, suggesting a symmetrical relationship between these processes.Movement of macromolecules in and out of the nucleus is a highly regulated process essential for proper progression though the cell cycle, response to extracellular signals, and viral maturation. Our knowledge of the mechanism by which proteins are imported into and RNAs exported from the nucleus has grown significantly in recent years. Proteins have been identified that mediate both inward and outward macromolecular movement and both processes appear to be regulated by some of the same factors (reviewed in refs. 1 and 2).Import of proteins into the nucleus is a highly conserved, multistep process initiated by recognition of a nuclear localization sequence (NLS) by a cognate receptor, followed by docking of the complex at the nuclear pore, and GTPdependent translocation into the nucleoplasm. The receptor for the canonical NLS is a heterodimeric protein complex variously called importin or karyopherin, composed of an ␣ (NLS-binding) and a ␤ (docking) subunit (3-6). Translocation through the nuclear pore is driven by GTP hydrolysis, catalyzed by the small ras-related GTP-binding protein Ran and its regulators (7-10). Once inside the nucleus, the importin͞ karyopherin complex is probably dissociated and the transport factors recycled to the cytoplasm (5). This relatively simple model fails to explain the nuclear import of proteins that lack an NLS conforming to the canonical sequences. The recent identification of a role for the importin ␤ homolog transportin, in the nuclear import of heterogeneous nuclear ribonucleoprotein (hnRNP) A1 raised the possibility that different classes of nuclear proteins would be transported by different pathways, defined by the identity of the ␤ subunit involved (11, 12).In contrast to protein import, how RNAs are exported from the nucleus to the cytoplasm is less well understood. Nascent RNA is subject to a number of posttranscriptional modifications, and it seems likely that RNA moves through the nucleoplasm and the nuclear pore...

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Regulation of mRNA export in response to stress in Saccharomyces cerevisiae.

Cited by 166 publications

References 68 publications

Structure of the C-terminus of the mRNA export factor Dbp5 reveals the interaction surface for the ATPase activator Gle1

Structure of the C-terminus of the mRNA export factor Dbp5 reveals the interaction surface for the ATPase activator Gle1

Hsp16p Is Required for Thermotolerance in Nuclear mRNA Export in Fission Yeast Schizosaccharomyces pombe

Importin/karyopherin protein family members required for mRNA export from the nucleus

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