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IGHMBP2 deletion suppresses translation and activates the integrated stress response

ABSTRACT: IGHMBP2 deletion suppresses translation and activates the integrated stress response

PROVIDER: PRJNA1046387 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR26979500.fastq.gz	Fastqsanger.gz
	SRR26979501.fastq.gz	Fastqsanger.gz
	SRR26979502.fastq.gz	Fastqsanger.gz
	SRR26979503.fastq.gz	Fastqsanger.gz
	SRR26979504.fastq.gz	Fastqsanger.gz

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IGHMBP2 deletion suppresses translation and activates the integrated stress response [Ribo-Seq]

Project description:IGHMBP2 deletion suppresses translation and activates the integrated stress response [Ribo-Seq]

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IGHMBP2 deletion suppresses translation and activates the integrated stress response [RNA-Seq]

Project description:IGHMBP2 deletion suppresses translation and activates the integrated stress response [RNA-Seq]

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IGHMBP2 deletion suppresses translation and activates the integrated stress response [Ribo-Seq]

Project description:IGHMBP2 is a non-essential, superfamily 1 DNA/RNA helicase with incompletely understood biological function. Mutagenesis in IGHMBP2 is found in patients with rare neuromuscular diseases SMARD1 and CMT2S. IGHMBP2 is implicated in translational and transcriptional regulation via biochemical association with ribosomal proteins, pre-rRNA processing factors, and tRNA-related species. To uncover the cellular consequences of perturbing IGHMBP2, we generated full and partial IGHMBP2 deletion K562 cell lines. We performed Ribo-seq and RNA-seq and identified diverse gene expression changes due to IGHMBP2 deletion, including ATF4 upregulation.

2023-12-19 | GSE248888 | GEO

IGHMBP2 deletion suppresses translation and activates the integrated stress response [RNA-Seq]

2023-12-19 | GSE248889 | GEO

IGHMBP2 deletion suppresses translation and activates the integrated stress response.

Project description:IGHMBP2 is a non-essential, superfamily 1 DNA/RNA helicase that is mutated in patients with rare neuromuscular diseases SMARD1 and CMT2S. IGHMBP2 is implicated in translational and transcriptional regulation via biochemical association with ribosomal proteins, pre-rRNA processing factors, and tRNA-related species. To uncover the cellular consequences of perturbing IGHMBP2, we generated full and partial IGHMBP2 deletion K562 cell lines. Using polysome profiling and a nascent protein synthesis assay, we found that IGHMBP2 deletion modestly reduces global translation. We performed Ribo-seq and RNA-seq and identified diverse gene expression changes due to IGHMBP2 deletion, including ATF4 upregulation. With recent studies showing the ISR can contribute to tRNA metabolism-linked neuropathies, we asked whether perturbing IGHMBP2 promotes ISR activation. We generated ATF4 reporter cell lines and found IGHMBP2 knockout cells demonstrate basal, chronic ISR activation. Our work expands upon the impact of IGHMBP2 in translation and elucidates molecular mechanisms that may link mutant IGHMBP2 to severe clinical phenotypes.

| S-EPMC10760061 | biostudies-literature

IGHMBP2 deletion suppresses translation and activates the integrated stress response

Project description:This SuperSeries is composed of the SubSeries listed below.

2023-12-18 | GSE248890 | GEO

RNA helicase Ighmbp2 regulates THO complex to ensure cellular mRNA homeostasis

Project description:RNA helicases constitute a large protein family implicated in cellular RNA homeostasis and disease development. Here we show that the RNA helicase Ighmbp2, linked to the neuromuscular disorder SMARD1 (DSMA1) associates with polysomes and impacts on translation of cellular mRNAs containing short, GC-rich and highly structured 5’UTRs. Absence of Ighmbp2 causes ribosome stalling at the start codon of target mRNAs, leading to their reduced translation efficiency. The main mRNA targets of Ighmbp2-mediated regulation encode for components of the THO complex that links mRNA production and nuclear export. Accordingly, failure of Ighmbp2 regulation of the THO complex causes perturbations of the cellular transcriptome and its encoded proteome. Ablation of essential THO complex subunits phenocopies these perturbations. Thus, Ighmbp2 is an upstream regulator of the THO complex that affects cellular mRNA homeostasis. Of note, Ighmbp2 dependent regulation of the THO complex is also observed in astrocytes derived from SMARD1 patients, suggesting that de-regulated mRNA metabolism contributes to SMARD1 etiology and offers new avenues for developing alternative therapeutics to treating SMARD1.

2024-01-18 | GSE237412 | GEO

Impaired local translation of β-actin mRNA in Ighmbp2-deficient motoneurons: implications for spinal muscular atrophy with respiratory distress (SMARD1)

Project description:Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is a fatal motoneuron disorder in children with unknown etiology. The disease is caused by mutations in the IGHMBP2 gene, encoding a Super Family 1 (SF1)-type RNA/DNA helicase. IGHMBP2 is a cytosolic protein that binds to ribosomes and polysomes, suggesting a role in mRNA metabolism. Here we performed morphological and functional analyses of isolated Ighmbp2-deficient motoneurons to address the question whether the SMARD1 phenotype results from de-regulation of protein biosynthesis. Ighmbp2-deficient motoneurons exhibited only moderate morphological aberrations such as a slight increase of axonal branches. Consistent with the rather mild phenotypic aberrations, RNA sequencing of Ighmbp2-deficient motoneurons revealed only minor transcriptome alterations compared to controls. Likewise, we did not detect any global changes in protein synthesis using pulsed SILAC (Stable Isotope Labeling by Amino acids in Cell culture), FUNCAT (FlUorescent Non–Canonical Amino acid Tagging) and SUnSET (SUrface SEnsing of Translation) approaches. However, we observed reduced β-actin protein levels at the growth cone of Ighmbp2-deficient motoneurons which was accompanied by reduced level of IMP1/ZBP1, a known interactor of β-actin mRNA. Fluorescence Recovery after Photobleaching (FRAP) studies revealed translational down-regulation of an eGFP-myr- β-actin 3’UTR mRNA in growth cones. Local translational regulation of β-actin mRNA was dependent on the 3’ UTR but independent of direct Ighmbp2-binding to β-actin mRNA. Taken together, our data indicate that Ighmbp2 deficiency results in local but modest disruption of protein biosynthesis which might partially contribute to the motoneuron defects seen in SMARD1.

2018-08-21 | GSE111224 | GEO

RNA helicase Ighmbp2 regulates THO complex to ensure cellular mRNA homeostasis

Project description:RNA helicases constitute a large protein family implicated in cellular RNA homeostasis and disease development. Here we show that the RNA helicase Ighmbp2, linked to the neuromuscular disorder SMARD1 (DSMA1) associates with polysomes and impacts on translation of cellular mRNAs containing short, GC-rich and highly structured 5’UTRs. Absence of Ighmbp2 causes ribosome stalling at the start codon of target mRNAs, leading to their reduced translation efficiency. The main mRNA targets of Ighmbp2-mediated regulation encode for components of the THO complex that links mRNA production and nuclear export. Accordingly, failure of Ighmbp2 regulation of the THO complex causes perturbations of the cellular transcriptome and its encoded proteome. Ablation of essential THO complex subunits phenocopies these perturbations. Thus, Ighmbp2 is an upstream regulator of the THO complex that impacts on cellular mRNA homeostasis. Of note, Ighmbp2 dependent regulation of the THO complex is also observed in astrocytes derived from DSMA1 patients, suggesting that de-regulated mRNA metabolism contributes to SMARD1 etiology.

2024-02-15 | PXD043336 | Pride

RNA helicase Ighmbp2 regulates THO complex to ensure cellular mRNA homeostasis

Project description:RNA helicases constitute a large protein family implicated in cellular RNA homeostasis and disease development. Here we show that the RNA helicase Ighmbp2, linked to the neuromuscular disorder SMARD1 associates with polysomes and impacts on translation of cellular mRNAs containing short, GC-rich and highly structured 5’UTRs. Using UV-crosslinking followed by RNAseq and BS3-crosslinking combined with mass spectrometry we were able to localize Ighmbp2 on ribosomes. Absence of Ighmbp2 causes ribosome stalling at the start codon of target mRNAs, leading to their reduced translation efficiency. The main mRNA targets of Ighmbp2-mediated regulation encode for components of the THO complex that links mRNA production and nuclear export. Accordingly, failure of Ighmbp2 regulation of the THO complex causes perturbations of the cellular transcriptome and its encoded proteome. Ablation of essential THO complex subunits phenocopies these perturbations. Thus, Ighmbp2 is an upstream regulator of the THO complex that affects cellular mRNA homeostasis. Of note, Ighmbp2-dependent regulation of the THO complex is also observed in astrocytes derived from SMARD1 patients, suggesting that de-regulated mRNA metabolism contributes to SMARD1 etiology and offers new avenues for developing alternative therapeutics to treating SMARD1.

2024-02-14 | PXD044048 | Pride

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