Cytoplasmic hGle1A regulates stress granules by modulation of translation

Aditi,; Folkmann, Andrew W.; Wente, Susan R.

doi:10.1091/mbc.e14-11-1523

Cited by 36 publications

(88 citation statements)

References 79 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…At 37°C, both GFP-hGle1-IVS14-2A>C and GFP-hIPK1 exhibited cytoplasmic steady state localization, with no apparent localization at the nuclear envelope or nucleoplasm (Figure 1). The cytoplasmic distribution of GFP-hGle1-IVS14-2A>C with exclusion from the nucleus was indistinguishable from previously reported hGle1A localization (Kendirgi et al, 2003; Kaneb et al, 2015; Aditi et al, 2015), and had no similarity to hGle1B localization (Kendirgi et al, 2003; Folkmann et al, 2013). Interestingly, as previously observed for both hGle1A and hGle1B, GFP-hGle1-IVS14-2A>C was recruited to SGs upon heat shock at 45°C (Figure 1).…”

Section: Resultscontrasting

confidence: 71%

“…Previously, we reported that hGle1 is a component of SGs and is required for SG assembly and disassembly (Aditi et al, 2015). Interestingly, hIPK1, the kinase required for producing hGle1’s cofactor IP 6 , also relocalizes to SGs upon stress (Brehm et al, 2007).…”

Section: Resultsmentioning

confidence: 99%

“…We recently found that hGle1A is required for proper SG assembly, disassembly and translational modulation (Aditi et al, 2015). The depletion of endogenous hGle1 from HeLa cells results in a striking decrease in the size and increase in the total population of SGs formed upon heat shock, as compared to control siRNA-treated cells.…”

Section: Resultsmentioning

confidence: 99%

“…The list of ALS-linked mutations in genes encoding mRNP components and modulators is rapidly expanding, and includes TAR DNA-binding protein 43 (TDP-43; Sreedharan et al, 2008), Fused in Sarcoma (FUS; Kwiatowski et al, 2009; Vance et al, 2009), hnRNP1 and hnRNPA2 (Kim et al, 2013), and, more recently, Gle1 (Kaneb et al 2015). Gle1 is a highly conserved and essential modulator of RNA-dependent DEAD-box ATPases during mRNA export (Alcazar-Roman et al, 2008; Murphy and Wente, 1996; Folkmann et al, 2013), translation (Bolger et al, 2008; Alcazar-Roman et al, 2010; Bolger and Wente, 2011) and stress granule dynamics (Aditi et al, 2015). By inducing the release of select RBPs, DEAD-box proteins facilitate changes in the mRNP protein composition through a process termed mRNP remodeling, and these mRNP changes play critical roles in an mRNA’s processing (Jarmoskaite and Russell, 2014).…”

Section: Introductionmentioning

confidence: 99%

“…The molecular mechanism of Gle1-stimulated DEAD-box activation at the NPC is largely based on the S. cerevisiae model system (Folkmann et al, 2011); however, our recent work shows that only the highly conserved Gle1B isoform, presumably in complex with the cofactor inositol hexakisphosphate (IP 6 ), is capable of activating the DEAD-box protein for mRNP remodeling during mRNA export (Folkmann et al, 2013). Conversely, the shorter hGle1A isoform lacking the hCG1-binding domain localizes primarily to the cytoplasm at steady state and is required for proper stress granule (SG) function (Aditi et al, 2015). Thus, the hGle1A and hGle1B isoforms exist in separate cellular pools and play multiple independent roles in regulating mRNPs, any one of which might be impacted in hGle1-associated ALS pathogenesis.…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

An amyotrophic lateral sclerosis-linked mutation in GLE1 alters the cellular pool of human Gle1 functional isoforms

Aditi

Glass

Dawson

et al. 2016

Advances in Biological Regulation

Self Cite

View full text Add to dashboard Cite

Amyotrophic lateral sclerosis (ALS) is a lethal late onset motor neuron disease with underlying cellular defects in RNA metabolism. In prior studies, two deleterious heterozygous mutations in the gene encoding human (h)Gle1 were identified in ALS patients. hGle1 is an mRNA processing modulator that requires inositol hexakisphosphate (IP6) binding for function. Interestingly, one hGLE1 mutation (c.1965-2A>C) results in a novel 88 amino acid C-terminal insertion, generating an altered protein. Like hGle1A, at steady state, the altered protein termed hGle1-IVS14-2A>C is absent from the nuclear envelope rim and localizes to the cytoplasm. hGle1A performs essential cytoplasmic functions in translation and stress granule regulation. Therefore, we speculated that the ALS disease pathology results from altered cellular pools of hGle1 and increased cytoplasmic hGle1 activity. GFP-hGle1-IVS14-2A>C localized to stress granules comparably to GFP-hGle1A, and rescued stress granule defects following siRNA-mediated hGle1 depletion. As described for hGle1A, overexpression of the hGle1-IVS14-2A>C protein also induced formation of larger SGs. Interestingly, hGle1A and the disease associated hGle1-IVS14-2A>C overexpression induced the formation of distinct cytoplasmic protein aggregates that appear similar to those found in neurodegenerative diseases. Strikingly, the ALS-linked hGle1-IVS14-2A>C protein also rescued mRNA export defects upon depletion of endogenous hGle1, acting in a potentially novel bi-functional manner. We conclude that the ALS-linked hGle1-c.1965-2A>C mutation generates a protein isoform capable of both hGle1A- and hGle1B-ascribed functions, and thereby uncoupled from normal mechanisms of hGle1 regulation.

show abstract

Section: Resultscontrasting

confidence: 71%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

An amyotrophic lateral sclerosis-linked mutation in GLE1 alters the cellular pool of human Gle1 functional isoforms

Aditi

Glass

Dawson

et al. 2016

Advances in Biological Regulation

Self Cite

View full text Add to dashboard Cite

show abstract

Survival beyond the perinatal period expands the phenotypes caused by mutations in GLE1

Said

Chong

Hempel

et al. 2017

American J of Med Genetics Pt A

View full text Add to dashboard Cite

Mutations in GLE1 underlie Lethal Congenital Contracture syndrome and Lethal Arthrogryposis with Anterior Horn Cell Disease. Both Lethal Congenital Contracture syndrome and Lethal Arthrogryposis with Anterior Horn Cell Disease are characterized by reduced fetal movements, congenital contractures, and a severe form of motor neuron disease that results in fetal death or death in the perinatal period, respectively. We identified bi-allelic mutations in GLE1 in two unrelated individuals with motor delays, feeding difficulties and respiratory insufficiency who survived beyond the perinatal period. Each affected child had missense variants predicted to result in amino acid substitutions near the C-terminus of GLE1 that are predicted to disrupt protein-protein interaction or GLE1 protein targeting. We hypothesize that mutations that preserve function of the coiled-coil domain of GLE1 cause Lethal Arthrogryposis with Anterior Horn Cell Disease whereas mutations that abolish the function of the coiled-coil domain cause Lethal Congenital Contracture syndrome. The phenotype of Lethal Arthrogryposis with Anterior Horn Cell Disease is now expanded to include multiple individuals surviving into childhood suggesting that Lethal Arthrogryposis with Anterior Horn Cell Disease is a misnomer and should be re-named Arthrogryposis with Anterior Horn Cell Disease.

show abstract

Stress Granules and ALS: A Case of Causation or Correlation?

Fernandes

Eshleman

Buchan

2018

Advances in Neurobiology

View full text Add to dashboard Cite

Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease characterized by cytoplasmic protein aggregates within motor neurons. These aggregates are linked to ALS pathogenesis. Recent evidence has suggested that stress granules may aid the formation of ALS protein aggregates. Here, we summarize current understanding of stress granules, focusing on assembly and clearance. We also assess the evidence linking alterations in stress granule formation and dynamics to ALS protein aggregates and disease pathology.

show abstract

Cytoplasmic hGle1A regulates stress granules by modulation of translation

Cited by 36 publications

References 79 publications

An amyotrophic lateral sclerosis-linked mutation in GLE1 alters the cellular pool of human Gle1 functional isoforms

An amyotrophic lateral sclerosis-linked mutation in GLE1 alters the cellular pool of human Gle1 functional isoforms

Survival beyond the perinatal period expands the phenotypes caused by mutations in GLE1

Stress Granules and ALS: A Case of Causation or Correlation?

Contact Info

Product

Resources

About