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Mutations in mRNA export mediator GLE1 result in a fetal motoneuron disease.

ABSTRACT: The most severe forms of motoneuron disease manifest in utero are characterized by marked atrophy of spinal cord motoneurons and fetal immobility. Here, we report that the defective gene underlying lethal motoneuron syndrome LCCS1 is the mRNA export mediator GLE1. Our finding of mutated GLE1 exposes a common pathway connecting the genes implicated in LCCS1, LCCS2 and LCCS3 and elucidates mRNA processing as a critical molecular mechanism in motoneuron development and maturation.

SUBMITTER: Nousiainen HO

PROVIDER: S-EPMC2684619 | biostudies-literature | 2008 Feb

REPOSITORIES: biostudies-literature

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Mutations in mRNA export mediator GLE1 result in a fetal motoneuron disease.

Nousiainen Heidi O HO Kestilä Marjo M Pakkasjärvi Niklas N Honkala Heli H Kuure Satu S Tallila Jonna J Vuopala Katri K Ignatius Jaakko J Herva Riitta R Peltonen Leena L

Nature genetics 20080120 2

The most severe forms of motoneuron disease manifest in utero are characterized by marked atrophy of spinal cord motoneurons and fetal immobility. Here, we report that the defective gene underlying lethal motoneuron syndrome LCCS1 is the mRNA export mediator GLE1. Our finding of mutated GLE1 exposes a common pathway connecting the genes implicated in LCCS1, LCCS2 and LCCS3 and elucidates mRNA processing as a critical molecular mechanism in motoneuron development and maturation. ...[more]

PMID: 18204449

Similar Datasets

Gle1 functions during mRNA export in an oligomeric complex that is altered in human disease.

Project description:The conserved multifunctional protein Gle1 regulates gene expression at multiple steps: nuclear mRNA export, translation initiation, and translation termination. A GLE1 mutation (FinMajor) is causally linked to human lethal congenital contracture syndrome-1 (LCCS1); however, the resulting perturbations on Gle1 molecular function were unknown. FinMajor results in a proline-phenylalanine-glutamine peptide insertion within the uncharacterized Gle1 coiled-coil domain. Here, we find that Gle1 self-associates both in vitro and in living cells via the coiled-coil domain. Electron microscopy reveals that high-molecular-mass Gle1 oligomers form ?26 nm diameter disk-shaped particles. With the Gle1-FinMajor protein, these particles are malformed. Moreover, functional assays document a specific requirement for proper Gle1 oligomerization during mRNA export, but not for Gle1's roles in translation. These results identify a mechanistic step in Gle1's mRNA export function at nuclear pore complexes and directly implicate altered export in LCCS1 disease pathology.

| S-EPMC3855398 | biostudies-literature

Insights into mRNA export-linked molecular mechanisms of human disease through a Gle1 structure-function analysis.

Project description:A critical step during gene expression is the directional export of nuclear messenger (m)RNA through nuclear pore complexes (NPCs) to the cytoplasm. During export, Gle1 in conjunction with inositol hexakisphosphate (IP6) spatially regulates the activity of the DEAD-box protein Dbp5 at the NPC cytoplasmic face. GLE1 mutations are causally linked to the human diseases lethal congenital contracture syndrome 1 (LCCS-1) and lethal arthrogryposis with anterior horn cell disease (LAAHD). Here, structure prediction and functional analysis provide strong evidence to suggest that the LCCS-1 and LAAHD disease mutations disrupt the function of Gle1 in mRNA export. Strikingly, direct fluorescence microscopy in living cells reveals a dramatic loss of steady-state NPC localization for GFP-gle1 proteins expressed from human gle1 genes harboring LAAHD and LCCS-1 mutations. The potential significance of these residues is further clarified by analyses of sequence and predicted structural conservation. This work offers insights into the perturbed mechanisms underlying human LCCS-1 and LAAHD disease states and emphasizes the potential impact of altered mRNA transport and gene expression in human disease.

| S-EPMC3932673 | biostudies-literature

The mRNA export factor Gle1 and inositol hexakisphosphate regulate distinct stages of translation.

Project description:Gene expression requires proper messenger RNA (mRNA) export and translation. However, the functional links between these consecutive steps have not been fully defined. Gle1 is an essential, conserved mRNA export factor whose export function is dependent on the small molecule inositol hexakisphosphate (IP(6)). Here, we show that both Gle1 and IP(6) are required for efficient translation termination in Saccharomyces cerevisiae and that Gle1 interacts with termination factors. In addition, Gle1 has a conserved physical association with the initiation factor eIF3, and gle1 mutants display genetic interactions with the eIF3 mutant nip1-1. Strikingly, gle1 mutants have defects in initiation, whereas strains lacking IP(6) do not. We propose that Gle1 functions together with IP(6) and the DEAD-box protein Dbp5 to regulate termination. However, Gle1 also independently mediates initiation. Thus, Gle1 is uniquely positioned to coordinate the mRNA export and translation mechanisms. These results directly impact models for perturbation of Gle1 function in pathophysiology.

| S-EPMC2601711 | biostudies-literature

Control of mRNA export and translation termination by inositol hexakisphosphate requires specific interaction with Gle1.

Project description:The unidirectional translocation of messenger RNA (mRNA) through the aqueous channel of the nuclear pore complex (NPC) is mediated by interactions between soluble mRNA export factors and distinct binding sites on the NPC. At the cytoplasmic side of the NPC, the conserved mRNA export factors Gle1 and inositol hexakisphosphate (IP(6)) play an essential role in mRNA export by activating the ATPase activity of the DEAD-box protein Dbp5, promoting localized messenger ribonucleoprotein complex remodeling, and ensuring the directionality of the export process. In addition, Dbp5, Gle1, and IP(6) are also required for proper translation termination. However, the specificity of the IP(6)-Gle1 interaction in vivo is unknown. Here, we characterize the biochemical interaction between Gle1 and IP(6) and the relationship to Dbp5 binding and stimulation. We identify Gle1 residues required for IP(6) binding and show that these residues are needed for IP(6)-dependent Dbp5 stimulation in vitro. Furthermore, we demonstrate that Gle1 is the primary target of IP(6) for both mRNA export and translation termination in vivo. In Saccharomyces cerevisiae cells, the IP(6)-binding mutants recapitulate all of the mRNA export and translation termination defects found in mutants depleted of IP(6). We conclude that Gle1 specifically binds IP(6) and that this interaction is required for the full potentiation of Dbp5 ATPase activity during both mRNA export and translation termination.

| S-EPMC2878036 | biostudies-literature

Nup42 and IP6 coordinate Gle1 stimulation of Dbp5/DDX19B for mRNA export in yeast and human cells.

Project description:The mRNA lifecycle is driven through spatiotemporal changes in the protein composition of mRNA particles (mRNPs) that are triggered by RNA-dependent DEAD-box protein (Dbp) ATPases. As mRNPs exit the nuclear pore complex (NPC) in Saccharomyces cerevisiae, this remodeling occurs through activation of Dbp5 by inositol hexakisphosphate (IP6 )-bound Gle1. At the NPC, Gle1 also binds Nup42, but Nup42's molecular function is unclear. Here we employ the power of structure-function analysis in S. cerevisiae and human (h) cells, and find that the high-affinity Nup42-Gle1 interaction is integral to Dbp5 (hDDX19B) activation and efficient mRNA export. The Nup42 carboxy-terminal domain (CTD) binds Gle1/hGle1B at an interface distinct from the Gle1-Dbp5/hDDX19B interaction site. A nup42-CTD/gle1-CTD/Dbp5 trimeric complex forms in the presence of IP6 . Deletion of NUP42 abrogates Gle1-Dbp5 interaction, and disruption of the Nup42 or IP6 binding interfaces on Gle1/hGle1B leads to defective mRNA export in S. cerevisiae and human cells. In vitro, Nup42-CTD and IP6 stimulate Gle1/hGle1B activation of Dbp5 and DDX19B recombinant proteins in similar, nonadditive manners, demonstrating complete functional conservation between humans and S. cerevisiae. Together, a highly conserved mechanism governs spatial coordination of mRNP remodeling during export. This has implications for understanding human disease mutations that perturb the Nup42-hGle1B interaction.

| S-EPMC5677552 | biostudies-literature

MKRN2 physically interacts with GLE1 to regulate mRNA export and zebrafish retinal development

Project description:The canonical mammalian mRNA export process is thought to terminate at the cytoplasmic face of the nuclear pore complex through mRNP remodeling. We conducted a stringent affinity-purification mass-spectrometry-based screen of the physical interactions of human RNA-binding E3 ubiquitin ligases. The resulting protein-interaction network revealed unexpected interactions between the RNA-binding E3 ubiquitin ligase MKRN2 and GLE1, a DEAD-box helicase activator implicated in mRNA export termination. We assessed MKRN2 epistasis with GLE1 in a genetically tractable zebrafish model. Strikingly, morpholino-mediated knockdown or CRISPR/Cas9-based knockout of MKRN2 partially rescued retinal developmental defects seen upon GLE1 depletion. Next, using iCLIP, we showed that MKRN2 binds preferentially to the 3'UTR of a diverse subset of mRNAs. Next-generation sequencing of fractionated cell extracts revealed that nuclear export of MKRN2-associated mRNAs is enhanced upon knockdown of MKRN2. Taken together, these results indicate that MKRN2 selectively interacts with GLE1 to regulate mRNA nuclear export and retinal development.

2020-05-19 | GSE136399 | GEO

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

Project description: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 A. 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 alpha-helix and a loop connecting beta5 and alpha4, 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.

| S-EPMC2752551 | biostudies-literature

Dbp5, Gle1-IP6 and Nup159: a working model for mRNP export.

Project description:Gene expression is a stepwise process involving distinct cellular processes including transcription, mRNA (mRNA) processing, mRNA export, and translation. As mRNAs are being synthesized, proteins associate with the RNA to form messenger ribonucleoprotein particles (mRNPs). Previous studies have demonstrated that the RNA-binding protein composition of these mRNPs is dynamic, changing as the mRNP moves through the different steps of gene expression, and playing a critical role in these events. An important step during this maturation process occurs at the cytoplasmic face of the nuclear pore complex (NPC) where the export protein Gle1 bound to inositol hexakisphosphate (IP 6) spatially activates the ATP-hydrolysis and mRNP-remodeling activity of the DEAD-box protein Dbp5. Recent work from our laboratory and others has provided important insights into the function and regulation of Dbp5. These include a more detailed explanation of the mechanism of Dbp5 RNP remodeling, the role of Gle1-IP6 in stimulating Dbp5 ATPase activity, and the identification of a novel paradigm for regulation of Dbp5 by Nup159. Based on in vitro biochemical assays, X-ray crystallography, and corresponding in vivo phenotypes, we propose here an updated model of the Dbp5 cycle during mRNP export through the NPC. This takes into account all available data and provides a platform for future studies.

| S-EPMC3324343 | biostudies-literature

MKRN2 physically interacts with GLE1 to regulate mRNA export and zebrafish retinal development (RNA-Seq)

2020-05-19 | GSE136421 | GEO

THOC2 Mutations Implicate mRNA-Export Pathway in X-Linked Intellectual Disability.

Project description:Export of mRNA from the cell nucleus to the cytoplasm is essential for protein synthesis, a process vital to all living eukaryotic cells. mRNA export is highly conserved and ubiquitous. Mutations affecting mRNA and mRNA processing or export factors, which cause aberrant retention of mRNAs in the nucleus, are thus emerging as contributors to an important class of human genetic disorders. Here, we report that variants in THOC2, which encodes a subunit of the highly conserved TREX mRNA-export complex, cause syndromic intellectual disability (ID). Affected individuals presented with variable degrees of ID and commonly observed features included speech delay, elevated BMI, short stature, seizure disorders, gait disturbance, and tremors. X chromosome exome sequencing revealed four missense variants in THOC2 in four families, including family MRX12, first ascertained in 1971. We show that two variants lead to decreased stability of THOC2 and its TREX-complex partners in cells derived from the affected individuals. Protein structural modeling showed that the altered amino acids are located in the RNA-binding domains of two complex THOC2 structures, potentially representing two different intermediate RNA-binding states of THOC2 during RNA transport. Our results show that disturbance of the canonical molecular pathway of mRNA export is compatible with life but results in altered neuronal development with other comorbidities.

| S-EPMC4573269 | biostudies-literature

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