Affinage

GLE1

mRNA export factor GLE1 · UniProt Q53GS7

Length
698 aa
Mass
79.8 kDa
Annotated
2026-06-10
48 papers in source corpus 29 papers cited in narrative 30 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GLE1 is a conserved, multifunctional regulator of RNA-dependent DEAD-box ATPases that governs directional mRNA export at the nuclear pore complex (NPC) and additionally tunes translation (PMID:16783363, PMID:21949122). At the cytoplasmic face of the NPC, GLE1 bound to inositol hexakisphosphate (IP6) activates the DEAD-box protein Dbp5: GLE1-IP6 promotes ATP binding to prime Dbp5 for RNA loading and accelerates the rate-limiting phosphate release step, thereby driving the mRNP-remodeling cycles required for export (PMID:16783363, PMID:16783364, PMID:21576266, PMID:35286399). Specific GLE1 residues mediate IP6 binding, and the same residues are required for Dbp5 stimulation in vitro and for mRNA export and translation termination in vivo, establishing IP6-bound GLE1 as the operative activating species (PMID:20371601). GLE1 is recruited to the NPC through its nucleoporin contacts—an N-terminal hNup155-binding domain and a C-terminal hCG1/Nup42-binding region that together with Dbp5 and IP6 assemble an activating complex—and through nucleocytoplasmic shuttling that is itself required for efficient poly(A)+ RNA export (PMID:14645504, PMID:16000379, PMID:28869701, PMID:12668658). GLE1 self-associates through a coiled-coil and an aggregation-prone region into disk-shaped oligomers; this oligomerization is specifically required for mRNA export but separable from its translation roles, and the disease-causing FinMajor insertion disrupts it (PMID:24243016, PMID:32981894). Beyond export, GLE1 acts as a translational gatekeeper by inhibiting the DEAD-box initiation factor Ded1 through reduction of its RNA-binding affinity, an IP6-independent activity, and cooperates with IP6 and Dbp5 in translation termination (PMID:21949122, PMID:28784717, PMID:18724935). An isoform-specific cytoplasmic function (Gle1A), regulated by ERK/JNK-primed GSK3 phosphorylation, controls stress-granule assembly and disassembly and modulates DDX3 activity, while GLE1 also influences transcription termination via DDX1 interactions and localizes to centrosomes to support microtubule organization (PMID:30429220, PMID:30262214, PMID:28035044, PMID:32755435). Loss-of-function GLE1 mutations cause lethal congenital contracture syndrome 1 and ALS-associated motor neuron pathology by depleting GLE1 from the NPC and disrupting oligomerization-dependent mRNA export (PMID:24243016, PMID:25343993).

Mechanistic history

Synthesis pass · year-by-year structured walk · 24 steps
  1. 2006 High

    Established the core biochemical function of GLE1: how an inositol phosphate cofactor and GLE1 jointly switch on the export ATPase Dbp5, resolving how nucleotide-dependent mRNP remodeling is activated at the pore.

    Evidence In vitro ATPase kinetics and in vitro IP6/protein binding with genetic suppression in yeast, replicated by two independent labs

    PMID:16783363 PMID:16783364

    Open questions at the time
    • Did not define the GLE1 residues mediating IP6 binding
    • Mechanism by which IP6 alters Dbp5 kinetics not yet resolved at the step level
  2. 2004 Medium

    Localized the IP6 requirement to the cytoplasmic face of the NPC, showing GLE1-dependent export operates spatially where mRNP is released.

    Evidence Genetic rescue with cytoplasm-restricted Ipk1 in gle1-2 ipk1-4 synthetic-lethal yeast

    PMID:15459192

    Open questions at the time
    • Single lab
    • Did not directly visualize the activating complex at the pore
  3. 2003 High

    Defined how GLE1 reaches the NPC—identifying a discrete Nup155-binding domain and nucleocytoplasmic shuttling as prerequisites for nuclear-rim localization and bulk mRNA export.

    Evidence Yeast two-hybrid, in vitro binding, deletion analysis, microinjection and FRAP in HeLa cells with mRNA export readout

    PMID:12668658 PMID:14645504

    Open questions at the time
    • Did not identify the shuttling receptor
    • Relationship between shuttling and Dbp5 activation not addressed
  4. 2005 High

    Identified the second nucleoporin anchor (hCG1/Nup42) and reconstituted a Nup155-Gle1B-hCG1 heterotrimer, showing both contacts are needed for NPC retention and efficient mRNA export.

    Evidence In vitro complex reconstitution, siRNA depletion of hCG1, mRNA export and protein production assays

    PMID:16000379

    Open questions at the time
    • Did not place hCG1 mechanistically in the Dbp5 activation cycle (resolved later)
    • Single lab for human system
  5. 2008 High

    Extended GLE1 function beyond export to translation, demonstrating roles in termination (with IP6) and initiation (via eIF3) that are partly IP6-independent.

    Evidence Genetic interaction analysis, reciprocal co-IP, in vivo translation termination and initiation assays in yeast

    PMID:18724935

    Open questions at the time
    • Molecular target of the initiation activity not identified here
    • Did not separate export from translation functions structurally
  6. 2009 High

    Provided the structural basis of the Gle1-Dbp5 interface, mapping surface residues whose mutation abolishes stimulation and cell viability.

    Evidence 1.8 Å crystal structure of Dbp5 C-terminal domain with structure-guided mutagenesis and in vitro/in vivo assays

    PMID:19805289

    Open questions at the time
    • No structure of the GLE1-IP6-Dbp5 complex
    • GLE1 conformation in the complex unresolved
  7. 2010 High

    Pinpointed GLE1 as the primary IP6 target, showing the IP6-binding residues are required for both export and translation termination in vivo.

    Evidence Structure-guided GLE1 point mutants in in vitro ATPase and in vivo export/termination assays in yeast

    PMID:20371601

    Open questions at the time
    • Did not address how IP6 binding feeds into the kinetic steps of Dbp5 cycling
  8. 2011 High

    Resolved the directionality of the Dbp5 cycle, dividing labor between GLE1-IP6 (ATP binding/RNA loading) and Nup159 (downstream release), and showed the Gle1-Dbp5 interaction is the limiting export step with sub-second pore dwell time.

    Evidence In vitro reconstitution ATPase assays, genetic suppressor bypass, dominant-negative competition, and FRAP in yeast and human cells

    PMID:21576265 PMID:21576266

    Open questions at the time
    • Mechanism of Nup159 action initially modeled as ADP release was later revised
    • Did not directly measure ATP-binding or Pi-release rate constants
  9. 2011 High

    Revealed that GLE1 acts oppositely on different DEAD-box proteins—inhibiting the initiation factor Ded1 in an IP6-independent manner—establishing GLE1 as a bidirectional ATPase regulator.

    Evidence In vitro ATPase and translation assays with genetic suppressor analysis (gle1-4 suppresses ded1-120)

    PMID:21949122

    Open questions at the time
    • Mechanism of Ded1 inhibition not yet defined (later shown to be via RNA binding)
  10. 2013 High

    Showed GLE1 self-assembles into oligomeric particles and that this oligomerization is selectively required for export but not translation, linking it directly to disease via the FinMajor mutation.

    Evidence In vitro self-association, EM, live-cell imaging, and separation-of-function mutants in export/translation assays

    PMID:24243016

    Open questions at the time
    • Atomic structure of the oligomer not determined
    • How oligomerization couples to Dbp5 activation unclear
  11. 2017 High

    Integrated the nucleoporin anchor into the activation mechanism, showing Nup42-CTD and IP6 non-additively stimulate GLE1 activation of Dbp5/DDX19B as part of a trimeric complex.

    Evidence In vitro trimeric complex reconstitution, ATPase assays, and export assays in yeast and human cells

    PMID:28869701

    Open questions at the time
    • Did not resolve a structure of the full activating assembly
  12. 2017 High

    Defined the molecular mechanism of Ded1 repression—GLE1 reduces Ded1 RNA affinity to act as a translation-initiation gatekeeper affecting preinitiation complex assembly.

    Evidence In vitro ATPase and RNA-binding assays, in vivo translation assays, genetic epistasis, preinitiation complex assays

    PMID:28784717

    Open questions at the time
    • Structural basis of the GLE1-Ded1 interaction unknown
  13. 2018 High

    Established phospho-regulation of cytoplasmic GLE1 (Gle1A), showing an ERK/JNK-primed, GSK3-driven phospho-code controls self-association, DDX3 activity, and stress-granule dynamics.

    Evidence Mass spectrometry, in vitro kinase assays, phosphomimetic/phosphodeficient mutants, ATPase assays, and stress-granule imaging in HeLa cells

    PMID:30429220

    Open questions at the time
    • In vivo physiological triggers of each kinase event not mapped
    • Single lab for stress-granule phenotypes
  14. 2018 Medium

    Assigned spatially distinct roles to the GLE1 isoforms—Gle1A in cytoplasmic stress-granule formation and survival, Gle1B at the nuclear envelope for export.

    Evidence Isoform-specific siRNA/overexpression with stress-granule imaging and survival assays in HeLa cells

    PMID:30262214

    Open questions at the time
    • Single lab
    • Endogenous isoform ratios and switching not quantified
  15. 2018 Medium

    Revised the Nup159 model, showing in solution kinetics that Nup159 does not accelerate ADP release but instead promotes GLE1 release from Dbp5.

    Evidence In vitro solution kinetic and thermodynamic nucleotide binding/release measurements

    PMID:29782832

    Open questions at the time
    • Single lab; contradicts earlier model and awaits independent reconciliation
    • In vivo relevance of the revised mechanism not tested directly
  16. 2020 Medium

    Dissected the two self-association determinants of GLE1 and their differential requirements across export, stress-granule formation, and stress translation.

    Evidence Mutagenesis of oligomerization domains with export, stress-granule, and translation readouts in HeLa cells

    PMID:32981894

    Open questions at the time
    • Single lab
    • Structural mechanism of the aggregation-prone region not resolved
  17. 2020 Medium

    Implicated GLE1 in transcription termination, showing shuttling inhibition causes 3'-UTR elongation, altered DDX1/CstF-64 interactions, and increased nuclear R-loops independent of export.

    Evidence Cell-permeable shuttling-disruption peptide, RNA-seq, immunofluorescence, and co-IP

    PMID:32755435

    Open questions at the time
    • Single lab
    • Direct enzymatic role of GLE1 in termination not established
  18. 2020 Medium

    Identified a new physical and functional partner, the E3 ligase MKRN2, with genetic epistasis linking GLE1 and MKRN2 in mRNA export and retinal development.

    Evidence AP-MS, zebrafish morpholino/CRISPR knockout rescue, ribonomic analysis

    PMID:32460013

    Open questions at the time
    • Single lab
    • Mechanistic basis of the GLE1-MKRN2 functional interaction unresolved
  19. 2022 High

    Provided the quantitative kinetic mechanism of Dbp5 activation, showing GLE1 thermodynamically traps the ATP-bound state and accelerates the rate-limiting Pi-release step.

    Evidence Stopped-flow and equilibrium ATPase kinetic analysis with yeast GLE1 and Dbp5

    PMID:35286399

    Open questions at the time
    • Single lab
    • Structural snapshots of the kinetic intermediates not obtained
  20. 2023 Medium

    Identified GLE1 T102 as a priming phosphosite that biases nuclear localization and modulates phosphatase-sensitive DDX1 association.

    Evidence Phospho-specific antibody, in vitro kinase assay, immunofluorescence, and co-IP

    PMID:37801910

    Open questions at the time
    • Single lab
    • Functional consequence of T102 phosphorylation for export/termination not directly tested
  21. 2024 Medium

    Extended GLE1-Dbp5 function to tRNA export, showing the Gle1-Dbp5 interface is required in vivo and that tRNA synergizes with GLE1 to fully activate Dbp5 ATPase activity.

    Evidence In vitro ATPase assays, dominant-negative overexpression, co-IP, and genetic epistasis in yeast

    PMID:38189406

    Open questions at the time
    • Single lab
    • Whether human GLE1 supports tRNA export not addressed
  22. 2015 Medium

    Connected GLE1 to motor neuron disease at the molecular level, characterizing an ALS-linked splice isoform with combined export and stress-granule functions.

    Evidence Molecular cloning, GFP-localization, siRNA rescue assays, and aggregate-formation analysis

    PMID:26776475

    Open questions at the time
    • Single lab
    • Pathogenic mechanism of the cytoplasmic aggregates not established
  23. 2014 Medium

    Demonstrated that ALS-linked GLE1 mutations deplete GLE1 from the NPC and fail to rescue motor neuron pathology, supporting haploinsufficiency as the disease mechanism.

    Evidence Fluorescence microscopy in HeLa and zebrafish morphant rescue assays

    PMID:25343993

    Open questions at the time
    • Single lab
    • Did not establish a mammalian in vivo model of the disease
  24. 2025 Low

    Provided a high-resolution structure of a fungal GLE1 ortholog, identifying secondary-structure elements potentially relevant to partner interactions.

    Evidence 1.5 Å X-ray crystallography of DhGle1ΔN with structural comparison to homologs

    PMID:40004126

    Open questions at the time
    • No functional mutagenesis validation
    • Fungal ortholog; relevance to human GLE1 interfaces not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How GLE1's distinct activities—export-coupled Dbp5 activation, Ded1/DDX3 inhibition, transcription termination, and centrosomal microtubule organization—are coordinated within a single cell, and the structure of the assembled GLE1-IP6-Dbp5-nucleoporin activating complex, remain unresolved.
  • No structure of the full activating complex
  • Mechanism integrating nuclear and cytoplasmic GLE1 functions unknown
  • Centrosomal role mechanistically uncharacterized at the molecular level

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 5 GO:0060090 molecular adaptor activity 3 GO:0008289 lipid binding 2 GO:0003723 RNA binding 1
Localization
GO:0005635 nuclear envelope 4 GO:0005829 cytosol 3 GO:0005634 nucleus 2 GO:0005815 microtubule organizing center 1
Pathway
R-HSA-8953854 Metabolism of RNA 4 R-HSA-392499 Metabolism of proteins 3 R-HSA-8953897 Cellular responses to stimuli 2 R-HSA-9609507 Protein localization 2
Partners
DBP5/DDX19BDDX1DDX3DED1MKRN2NAB2NUP155NUP42
Complex memberships
Gle1 coiled-coil homo-oligomerGle1-IP6-Dbp5 activating complexNup155-Gle1B-hCG1/Nup42 NPC complex

Evidence

Reading pass · 30 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 Gle1 and inositol hexakisphosphate (InsP6) together stimulate the RNA-dependent ATPase activity of the DEAD-box protein Dbp5 at the nuclear pore complex. In vitro kinetic analysis showed InsP6 significantly increased Dbp5 ATPase activity in a Gle1-dependent manner and lowered the effective RNA concentration for half-maximal ATPase activity. Gle1 alone had minimal stimulatory effect. Maximal InsP6 binding required both Dbp5 and Gle1. In vitro ATPase kinetic assays, genetic suppression (overexpression of DBP5 suppressed mRNA export defects of ipk1 nup42 mutant) Nature cell biology High 16783363
2006 Gle1 directly binds InsP6 and this binding potentiates Gle1-mediated stimulation of Dbp5 ATPase and RNA-binding activities. A gle1 point mutant deficient for Dbp5 stimulation in vitro displays an mRNA export defect in vivo, establishing that Dbp5 activation is an essential function of Gle1. In vitro ATPase and RNA-binding assays, in vitro binding, dominant mutations in DBP5 and GLE1 that rescue InsP6-deficient mRNA export phenotypes, in vivo mRNA export assays Nature cell biology High 16783364
2008 Gle1 and IP6 are required for efficient translation termination in S. cerevisiae; Gle1 physically interacts with translation termination factors. Additionally, Gle1 has a conserved physical association with the initiation factor eIF3, and gle1 mutants display genetic interactions with the eIF3 mutant nip1-1. gle1 mutants have defects in translation initiation independently of IP6. Genetic interaction analysis, co-immunoprecipitation (Gle1-eIF3 interaction), in vivo translation termination and initiation assays in yeast mutants Cell High 18724935
2010 Specific Gle1 residues are required for IP6 binding, and these same residues are needed for IP6-dependent Dbp5 stimulation in vitro. In vivo, IP6-binding mutants of Gle1 recapitulate all mRNA export and translation termination defects seen in IP6-depleted cells, establishing Gle1 as the primary target of IP6 for both processes. In vitro ATPase stimulation assays with Gle1 point mutants, in vivo mRNA export and translation termination assays in S. cerevisiae The Journal of biological chemistry High 20371601
2011 Nup159 is specifically required for ADP release from Dbp5, whereas Gle1-IP6 stimulates ATP binding to Dbp5, priming it for RNA loading. A Dbp5 mutant with reduced ADP binding bypasses the need for Nup159 interaction in vivo. Together, Nup159 and Gle1-IP6 regulate Dbp5 cycles by controlling its nucleotide-bound state, allowing multiple cycles of mRNP remodeling at the NPC. In vitro reconstitution ATPase assays, genetic suppressor analysis (dbp5-R256D/R259D bypass of Nup159), in vivo mRNA export assays Genes & development High 21576266
2011 ATP binding and hydrolysis are required for efficient Dbp5 association with NPCs. RNA-binding-deficient Dbp5 mutants are dominant-negative for mRNA export by competing with wild-type Dbp5 for Gle1 at NPCs. The Dbp5-Gle1 interaction is limiting for export and can be independent of Nup159. FRAP shows Dbp5 associates with NPCs for less than 1 second on average. Dominant-negative mutant analysis in yeast and human cells, FRAP (fluorescence recovery after photobleaching), in vivo mRNA export assays Genes & development High 21576265
2011 Gle1 physically and genetically interacts with the DEAD-box protein Ded1 (a translation initiation factor). Unlike its stimulation of Dbp5, Gle1 inhibits Ded1 ATPase activity in vitro, and this inhibition is independent of IP6. A gle1-4 mutant suppresses translation initiation defects in ded1-120 mutant. Gle1 inhibits translation in vitro in competent extracts. In vitro ATPase assay (Gle1 inhibition of Ded1), genetic suppressor analysis (gle1-4 suppresses ded1-120), in vitro translation assay The Journal of biological chemistry High 21949122
2003 The N-terminal 29 residues of hGle1 constitute the hNup155-binding domain. The hGle1-hNup155 interaction is necessary for NPC localization of hGle1. hNup155 C-terminal 177 amino acids bind hGle1. Deletion of the N-terminal 29 residues of hGle1B abolished nuclear rim localization in HeLa cells. Yeast two-hybrid screen, in vitro binding assay, deletion analysis, fluorescence microscopy in HeLa cells Molecular & cellular proteomics Medium 14645504
2003 hGle1 undergoes nucleocytoplasmic shuttling between the nucleus and cytoplasm. An internal 39-amino acid shuttling domain is necessary and sufficient for nucleocytoplasmic transport. Disruption of shuttling by a cell-permeable peptide impairs export of bulk poly(A)+ RNA and specific mRNA and reduces hGle1 localization at the nuclear envelope. Microinjection of recombinant hGle1, FRAP in live HeLa cells expressing EGFP-hGle1, cell-permeable peptide inhibition, mRNA export assay The Journal of cell biology High 12668658
2005 The unique C-terminal 43 amino acid region of hGle1B mediates binding to the C-terminal non-FG region of nucleoporin hCG1/NPL1. hNup155, hGle1B, and hCG1 form a heterotrimeric complex in vitro. siRNA-mediated depletion of hCG1 causes hGle1 accumulation in cytoplasmic foci and inhibits Hsp70 mRNA export and Hsp70 protein production. In vitro binding assay (heterotrimeric complex reconstitution), siRNA knockdown, mRNA export assay, fluorescence microscopy Molecular biology of the cell High 16000379
2004 Nab2, Gfd1, and Gle1 associate in a complex. Direct in vitro binding assay revealed a direct association between Nab2 and Gfd1. Nuclear export of Nab2 was blocked in a gle1 mutant at the restrictive temperature, placing Gle1 in the pathway for Nab2-bound mRNA export. Affinity isolation with recombinant proteins from yeast lysates, co-immunoprecipitation, in vitro binding assay, in vivo export assay in gle1 temperature-sensitive mutant The Journal of biological chemistry Medium 15208322
2004 Cytoplasmic production of IP6 by plasma membrane-anchored Ipk1 is sufficient to rescue mRNA export defects of a gle1-2 ipk1-4 synthetic lethal mutant, establishing that the IP6 requirement for Gle1-mediated mRNA export operates at the cytoplasmic face of the NPC. Genetic rescue (cytoplasm-restricted Ipk1 complementation of gle1-2 ipk1-4 synthetic lethal), spatial restriction of IP6-producing enzymes The Journal of biological chemistry Medium 15459192
2009 Crystal structure of the C-terminal domain of Dbp5 (1.8 Å) revealed a RecA-like fold with a unique C-terminal alpha-helix and a loop connecting beta5 and alpha4 not present in other DExD/H-box proteins. Structure-guided mutagenesis identified charged surface residues whose mutation weakens Gle1 binding and inhibits Gle1-stimulated Dbp5 ATPase activity in vitro; the same mutations were unable to support yeast growth, demonstrating that Gle1-Dbp5 interaction is required for cellular mRNA export. X-ray crystallography (1.8 Å), structure-guided mutagenesis, in vitro ATPase stimulation assay, in vivo growth complementation assay Proceedings of the National Academy of Sciences of the United States of America High 19805289
2013 Gle1 self-associates via its coiled-coil domain both in vitro and in living cells, forming ~26 nm diameter disk-shaped oligomeric particles visible by electron microscopy. The disease-causing FinMajor mutation (proline-phenylalanine-glutamine insertion) disrupts proper Gle1 oligomer formation. Correct Gle1 oligomerization is specifically required for mRNA export function but not for Gle1's roles in translation. In vitro self-association assay, live-cell imaging (fluorescence), electron microscopy, functional mRNA export and translation assays with oligomerization-deficient mutants Cell High 24243016
2017 The Nup42 C-terminal domain (CTD) binds Gle1/hGle1B at an interface distinct from the Gle1-Dbp5 interaction site. A trimeric Nup42-CTD/Gle1-CTD/Dbp5 complex forms in the presence of IP6. Deletion of NUP42 abrogates the Gle1-Dbp5 interaction. In vitro, Nup42-CTD and IP6 stimulate Gle1/hGle1B activation of Dbp5 and hDDX19B in similar, non-additive manners. Disruption of the Nup42 or IP6 binding interfaces on Gle1/hGle1B causes defective mRNA export in yeast and human cells. In vitro ATPase stimulation assay, trimeric complex reconstitution, genetic deletion analysis, mRNA export assay in yeast and human cells, structure-function mutagenesis Traffic (Copenhagen, Denmark) High 28869701
2017 Gle1 inhibits Ded1 RNA binding to reduce Ded1 ATPase activity and repress translation, acting as a gatekeeper to optimize Ded1 activity. Mutation analysis and binding assays show Gle1 inhibits Ded1 by reducing its affinity for RNA. Both Ded1 and Gle1 affect assembly of preinitiation complexes. In vitro ATPase assay, RNA-binding assay, in vivo translation assays, genetic epistasis (GLE1 suppression of DED1 overexpression defects), preinitiation complex assembly assay Molecular and cellular biology High 28784717
2018 Human Gle1 is regulated by phosphorylation during heat shock stress. MS identified 14 phosphorylation sites in Gle1A, with six clustering in an N-terminal intrinsically disordered region. ERK and JNK phosphorylate the Gle1A N-terminal domain, priming it for glycogen synthase kinase 3 (GSK3) phosphorylation. A phosphomimetic gle1A6D variant perturbed self-association and inhibited DDX3 ATPase activity. Phosphodeficient GFP-gle1A6A promoted stress granule assembly, whereas GFP-gle1A6D enhanced stress granule disassembly. Mass spectrometry (phosphosite identification), in vitro kinase assay (ERK, JNK, GSK3), phosphomimetic and phosphodeficient mutant analysis, in vitro ATPase assay (DDX3 inhibition), stress granule imaging in HeLa cells The Journal of biological chemistry High 30429220
2018 Gle1A isoform is required for proper stress granule formation and the sodium arsenite survival response in HeLa cells. Gle1B functions in mRNA export at the nuclear pore complex. The two isoforms have spatially distinct functions: Gle1A in cytoplasmic stress granules, Gle1B at the nuclear envelope. siRNA knockdown of hGle1, overexpression of Gle1A isoform, stress granule imaging, cell survival assay Advances in biological regulation Medium 30262214
2016 Gle1 localizes to centrosomes and basal bodies, assembling into the toroid-shaped pericentriolar material around the mother centriole. Reduced Gle1 levels correlate with decreased pericentrin localization and microtubule organization defects independently of mRNA export loss. In Gle1-depleted zebrafish, Kupffer's vesicle shows compromised ciliary beating and developmental defects. Fluorescence microscopy (localization), siRNA/morpholino knockdown, centrosome/microtubule phenotype analysis, zebrafish ciliary beating assay Molecular biology of the cell Medium 28035044
2022 Gle1 activates Dbp5 by two mechanisms: (1) Gle1 binding to Dbp5-ATP is thermodynamically coupled, with Gle1 binding Dbp5-ATP >100-fold more tightly than other nucleotide states, slowing ATP dissociation >150-fold; (2) Gle1 accelerates the rate-limiting phosphate (Pi) release step ~20-fold. These activities ensure a pool of ATP-bound Dbp5 at NPCs for RNA engagement during export. In vitro kinetic and equilibrium ATPase analysis (stopped-flow, fluorescence-based assays) with S. cerevisiae Gle1 and Dbp5 Nucleic acids research High 35286399
2018 Nup159 did not accelerate ADP release from Dbp5, contradicting the proposed nucleotide exchange factor model. Instead, Gle1 slowed ADP release from Dbp5 independent of Mg2+. In the presence of Nup159, the Gle1-ADP-Dbp5 interaction was reduced ~18-fold, suggesting Nup159 promotes Gle1 release from Dbp5 rather than ADP release. In vitro solution-based kinetic and thermodynamic assays (nucleotide binding/release measurements) Journal of molecular biology Medium 29782832
2020 Gle1 self-association is driven by two distinct regions: a coiled-coil domain and a novel 10-amino acid aggregation-prone region. Gle1 oligomerization is necessary for mRNA export and stress granule formation (additively requiring both domains) and for translation regulation under stress (each domain independently required). Gle1 self-association is dispensable for phosphorylation and non-stressed translation initiation. Mutagenesis of oligomerization domains, exogenous expression in HeLa cells, mRNA export assay, stress granule imaging, translation assay The Journal of biological chemistry Medium 32981894
2020 Gle1 physically interacts with the RNA-binding E3 ubiquitin ligase MKRN2. In zebrafish, morpholino knockdown or CRISPR/Cas9 knockout of MKRN2 partially rescues retinal developmental defects caused by GLE1 depletion, establishing a functional epistatic relationship between GLE1 and MKRN2 in mRNA export and retinal development. Affinity-purification mass spectrometry (interaction identification), morpholino knockdown, CRISPR/Cas9 knockout, zebrafish genetic epistasis (rescue assay), ribonomic analysis Cell reports Medium 32460013
2020 Nuclear accumulation of Gle1 (via shuttling inhibition) results in accumulation of specific mRNAs with elongated 3'-UTRs due to altered transcription termination, not altered nuclear export. Gle1 shuttling inhibition increased DDX1 nucleoplasmic localization and decreased DDX1 interactions with Gle1 and with CstF-64 (pre-mRNA cleavage stimulation factor). Gle1 colocalized with nuclear R-loops, and shuttling inhibition increased nuclear R-loop signal intensity. Cell-permeable peptide to disrupt shuttling, RNA-seq/mRNA accumulation analysis, immunofluorescence (DDX1, R-loop localization), co-immunoprecipitation (Gle1-DDX1-CstF-64 interaction) Molecular biology of the cell Medium 32755435
2023 Phosphorylation of Gle1 at threonine 102 (T102) serves as a priming event for further N-terminal phosphorylation. Basally phosphorylated (T102) Gle1 is predominantly nuclear; under sodium arsenite stress, more cytoplasmic localization is detected. Gle1-pT102 co-immunoprecipitates with DDX1 in a phosphatase-sensitive manner. Disruption of Gle1 nucleocytoplasmic shuttling decreased total Gle1-DDX1 association but increased co-isolation of Gle1-pT102 with DDX1. Phospho-specific antibody generation, in vitro kinase assay, indirect immunofluorescence microscopy, co-immunoprecipitation Advances in biological regulation Medium 37801910
2024 Gle1 binding to Dbp5 (via the Gle1-Dbp5 interaction interface) is required for Dbp5 to mediate tRNA export in vivo, as shown by dominant-negative Dbp5 mutants. tRNA acts synergistically with Gle1 to fully activate Dbp5 ATPase activity; direct Dbp5-tRNA interaction alone does not stimulate ATPase activity. In vitro ATPase assay (Dbp5 + tRNA ± Gle1), dominant-negative overexpression in vivo, co-immunoprecipitation (Dbp5-tRNA), genetic epistasis (dbp5 mutants parallel to los1) eLife Medium 38189406
2005 hGle1 localization to nuclear pore complexes requires interaction with hCG1 (via the unique C-terminal 43 aa of hGle1B); siRNA-mediated depletion of hCG1 causes hGle1 accumulation in cytoplasmic foci, indicating hCG1 is required for NPC localization of hGle1. This parallels the yeast Gle1-Nup42/Rip1 interaction. siRNA knockdown, fluorescence microscopy, in vitro binding/complex assembly assay Molecular biology of the cell Medium 16000379
2015 An ALS-linked hGLE1 splice site mutation (c.1965-2A>C) generates a novel protein isoform (hGle1-IVS14-2A>C) with an 88 amino acid C-terminal insertion. This isoform localizes to stress granules (like hGle1A), rescues stress granule defects upon hGle1 depletion, and can also rescue mRNA export defects — acting in a bi-functional manner combining hGle1A and hGle1B functions. Both hGle1A and hGle1-IVS14-2A>C overexpression induced cytoplasmic protein aggregates. Molecular cloning of mutant isoform, GFP-tagged localization by fluorescence microscopy, siRNA rescue assay (stress granule and mRNA export), overexpression aggregate formation Advances in biological regulation Medium 26776475
2014 Two deleterious ALS-linked hGLE1 mutations cause depletion of hGle1 from the nuclear pore in HeLa cells and fail to rescue motor neuron pathology in zebrafish morphants lacking Gle1, consistent with haploinsufficiency as the ALS mechanism. Fluorescence microscopy (hGle1 nuclear pore localization in HeLa), zebrafish morphant rescue assay Human molecular genetics Medium 25343993
2025 Crystal structure of N-terminally truncated Gle1 from Debaryomyces hansenii (DhGle1ΔN) was determined at 1.5 Å resolution, revealing 13 α-helices. Structural comparison with homologs showed no significant conformational changes upon complex formation, but identified distinct secondary structural elements in α1, α3, α4, and α8 that may be relevant to partner interactions. X-ray crystallography (1.5 Å), structural comparison with homologs International journal of molecular sciences Low 40004126

Source papers

Stage 0 corpus · 48 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 Inositol hexakisphosphate and Gle1 activate the DEAD-box protein Dbp5 for nuclear mRNA export. Nature cell biology 239 16783363
2006 Activation of the DExD/H-box protein Dbp5 by the nuclear-pore protein Gle1 and its coactivator InsP6 is required for mRNA export. Nature cell biology 226 16783364
2008 Mutations in mRNA export mediator GLE1 result in a fetal motoneuron disease. Nature genetics 155 18204449
2008 The mRNA export factor Gle1 and inositol hexakisphosphate regulate distinct stages of translation. Cell 127 18724935
2014 Deleterious mutations in the essential mRNA metabolism factor, hGle1, in amyotrophic lateral sclerosis. Human molecular genetics 116 25343993
2011 The Dbp5 cycle at the nuclear pore complex during mRNA export II: nucleotide cycling and mRNP remodeling by Dbp5 are controlled by Nup159 and Gle1. Genes & development 93 21576266
2011 The Dbp5 cycle at the nuclear pore complex during mRNA export I: dbp5 mutants with defects in RNA binding and ATP hydrolysis define key steps for Nup159 and Gle1. Genes & development 91 21576265
2011 Dbp5, Gle1-IP6 and Nup159: a working model for mRNP export. Nucleus (Austin, Tex.) 87 22064466
2013 Gle1 functions during mRNA export in an oligomeric complex that is altered in human disease. Cell 71 24243016
2010 Control of mRNA export and translation termination by inositol hexakisphosphate requires specific interaction with Gle1. The Journal of biological chemistry 71 20371601
2005 Interaction between the shuttling mRNA export factor Gle1 and the nucleoporin hCG1: a conserved mechanism in the export of Hsp70 mRNA. Molecular biology of the cell 71 16000379
2003 The mRNA export factor human Gle1 interacts with the nuclear pore complex protein Nup155. Molecular & cellular proteomics : MCP 55 14645504
2003 An essential role for hGle1 nucleocytoplasmic shuttling in mRNA export. The Journal of cell biology 52 12668658
2012 A zebrafish model of lethal congenital contracture syndrome 1 reveals Gle1 function in spinal neural precursor survival and motor axon arborization. Development (Cambridge, England) 47 22357925
2004 Cytoplasmic inositol hexakisphosphate production is sufficient for mediating the Gle1-mRNA export pathway. The Journal of biological chemistry 45 15459192
2017 Nup42 and IP6 coordinate Gle1 stimulation of Dbp5/DDX19B for mRNA export in yeast and human cells. Traffic (Copenhagen, Denmark) 40 28869701
2011 Gle1 is a multifunctional DEAD-box protein regulator that modulates Ded1 in translation initiation. The Journal of biological chemistry 39 21949122
2004 Nuclear export of the yeast mRNA-binding protein Nab2 is linked to a direct interaction with Gfd1 and to Gle1 function. The Journal of biological chemistry 32 15208322
2016 A role for Gle1, a regulator of DEAD-box RNA helicases, at centrosomes and basal bodies. Molecular biology of the cell 31 28035044
2009 Structure of the C-terminus of the mRNA export factor Dbp5 reveals the interaction surface for the ATPase activator Gle1. Proceedings of the National Academy of Sciences of the United States of America 30 19805289
2015 Restoration of miR-127-3p and miR-376a-3p counteracts the neoplastic phenotype of giant cell tumor of bone derived stromal cells by targeting COA1, GLE1 and PDIA6. Cancer letters 26 26655997
2013 Insights into mRNA export-linked molecular mechanisms of human disease through a Gle1 structure-function analysis. Advances in biological regulation 26 24275432
2015 An amyotrophic lateral sclerosis-linked mutation in GLE1 alters the cellular pool of human Gle1 functional isoforms. Advances in biological regulation 24 26776475
2018 MAPK- and glycogen synthase kinase 3-mediated phosphorylation regulates the DEAD-box protein modulator Gle1 for control of stress granule dynamics. The Journal of biological chemistry 22 30429220
2017 Gle1 Regulates RNA Binding of the DEAD-Box Helicase Ded1 in Its Complex Role in Translation Initiation. Molecular and cellular biology 20 28784717
2018 Depletion of mRNA export regulator DBP5/DDX19, GLE1 or IPPK that is a key enzyme for the production of IP6, resulting in differentially altered cytoplasmic mRNA expression and specific cell defect. PloS one 19 29746542
2017 Expansion of the GLE1-associated arthrogryposis multiplex congenita clinical spectrum. Clinical genetics 16 27684565
2018 Gle1 mediates stress granule-dependent survival during chemotoxic stress. Advances in biological regulation 15 30262214
2020 MKRN2 Physically Interacts with GLE1 to Regulate mRNA Export and Zebrafish Retinal Development. Cell reports 14 32460013
2022 The nucleoporin Gle1 activates DEAD-box protein 5 (Dbp5) by promoting ATP binding and accelerating rate limiting phosphate release. Nucleic acids research 11 35286399
2017 Survival beyond the perinatal period expands the phenotypes caused by mutations in GLE1. American journal of medical genetics. Part A 11 28884921
2018 Nup159 Weakens Gle1 Binding to Dbp5 But Does Not Accelerate ADP Release. Journal of molecular biology 10 29782832
2020 Functions of Gle1 are governed by two distinct modes of self-association. The Journal of biological chemistry 9 32981894
2016 A mitotic nuclear envelope tether for Gle1 also impacts nuclear and nucleolar architecture. Molecular biology of the cell 9 27630260
2016 Deficiency in the mRNA export mediator Gle1 impairs Schwann cell development in the zebrafish embryo. Neuroscience 8 26921650
2017 The importance of managing the patient and not the gene: expanded phenotype of GLE1-associated arthrogryposis. Cold Spring Harbor molecular case studies 6 28729373
2008 Gle1 does double duty. Cell 6 18724928
2017 A homozygous I684T in GLE1 as a novel cause of arthrogryposis and motor neuron loss. Clinical genetics 5 28657126
2020 Nucleocytoplasmic shuttling of Gle1 impacts DDX1 at transcription termination sites. Molecular biology of the cell 4 32755435
2020 Extension of the phenotypic spectrum of GLE1-related disorders to a mild congenital form resembling congenital myopathy. Molecular genetics & genomic medicine 3 32537934
2019 Correction: Depletion of mRNA export regulator DBP5/DDX19, GLE1 or IPPK that is a key enzyme for the production of IP6, resulting in differentially altered cytoplasmic mRNA expression and specific cell defect. PloS one 3 31344122
2024 Gle1 is required for tRNA to stimulate Dbp5 ATPase activity in vitro and promote Dbp5-mediated tRNA export in vivo in Saccharomyces cerevisiae. eLife 2 38189406
2021 Mutation Screening of the GLE1 Gene in a Large Chinese Cohort of Amyotrophic Lateral Sclerosis Patients. Frontiers in neuroscience 2 34025336
2018 Screening of GLE1 mutations in Chinese amyotrophic lateral sclerosis patients. Neurobiology of aging 2 29398120
2023 Gle1 is required for tRNA to stimulate Dbp5 ATPase activity in vitro and to promote Dbp5 mediated tRNA export in vivo. bioRxiv : the preprint server for biology 1 37425677
2018 The expression of SMN1, MART3, GLE1 and FUS genes in spinal muscular atrophy. Folia histochemica et cytobiologica 1 30565205
2025 Molecular Structure of the mRNA Export Factor Gle1 from Debaryomyces hansenii. International journal of molecular sciences 0 40004126
2023 Phosphorylation impacts GLE1 nuclear localization and association with DDX1. Advances in biological regulation 0 37801910

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