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IGHMBP2 deletion suppresses translation and activates the integrated stress response

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE248890 | GEO | 2023/12/18

REPOSITORIES: GEO

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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 [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 deletion suppresses translation and activates the integrated stress response

| PRJNA1046387 | ENA

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]

| PRJNA1046391 | ENA

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]

| PRJNA1046396 | ENA

Senescence suppresses the integrated stress response and activates a stress-enhanced secretory phenotype.

Project description:Senescence is a state of indefinite cell cycle arrest associated with aging, cancer, and age-related diseases. Here, using label-based mass spectrometry, ribosome profiling and nanopore direct RNA sequencing, we explore the coordinated interaction of translational and transcriptional programs of human cellular senescence. We find that translational deregulation and a corresponding maladaptive integrated stress response (ISR) is a hallmark of senescence that desensitizes senescent cells to stress. We present evidence that senescent cells maintain high levels of eIF2α phosphorylation, typical of ISR activation, but translationally repress production of the stress response transcription factor 4 (ATF4) by ineffective bypass of the inhibitory upstream open reading frames. Surprisingly, ATF4 translation remains inhibited even after acute proteotoxic and amino acid starvation stressors, resulting in a highly diminished stress response. Furthermore, absent a response, stress augments the senescence secretory phenotype, thus intensifying a proinflammatory state that exacerbates disease. Our results reveal a novel mechanism that senescent cells exploit to evade an adaptive stress response and remain viable.

| S-EPMC10441410 | biostudies-literature

Trans-10, cis-12 conjugated linoleic acid activates the integrated stress response pathway in adipocytes

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

2008-05-09 | GSE11384 | GEO

Mutations in tRNA synthetases impair translation and activate the integrated stress response in inherited peripheral neuropathie

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

2020-02-11 | GSE145006 | GEO

PI3Kδ activates E2F1 synthesis in response to mRNA translation stress.

Project description:The c-myc oncogene stimulates ribosomal biogenesis and protein synthesis to promote cellular growth. However, the pathway by which cells sense and restore dysfunctional mRNA translation and how this is linked to cell proliferation and growth is not known. We here show that mRNA translation stress in cis triggered by the gly-ala repeat sequence of Epstein-Barr virus (EBV)-encoded EBNA1, results in PI3Kδ-dependent induction of E2F1 mRNA translation with the consequent activation of c-Myc and cell proliferation. Treatment with a specific PI3Kδ inhibitor Idelalisib (CAL-101) suppresses E2F1 and c-Myc levels and causes cell death in EBNA1-induced B cell lymphomas. Suppression of PI3Kδ prevents E2F1 activation also in non-EBV-infected cells. These data illustrate an mRNA translation stress-response pathway for E2F1 activation that is exploited by EBV to promote cell growth and proliferation, offering new strategies to treat EBV-carrying cancers.

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