ArticleMolecular and cellular biology2012
A novel feedback loop regulates the response to endoplasmic reticulum stress via the cooperation of cytoplasmic splicing and mRNA translation.
Article in Molecular and cellular biology, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 45 papers.
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Who cites it
45 citing papers in PubMed, 85 citations in OpenAlex.
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- Unfolded Protein Response Pathways in Cancer: Mechanisms, Tumor Biology and Therapeutic Opportunities.Molecular diagnosis & therapy · 2026Review
- Fbxo42 promotes the degradation of Ataxin-2 granules to trigger terminal Xbp1 signaling.Nature communications · 2025Article
- NOXA exacerbates endoplasmic-reticulum-stress-induced intervertebral disc degeneration by activating apoptosis and ECM degradation.Cell death discovery · 2025Article
- A neurodegenerative cellular stress response linked to dark microglia and toxic lipid secretion.Neuron · 2025Article
- Gene Expression Profiling Reveals Fundamental Sex-Specific Differences in SIRT3-Mediated Redox and Metabolic Signaling in Mouse Embryonic Fibroblasts.International journal of molecular sciences · 2024Article
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- Transcriptomics and Phenotypic Analysis ofInternational journal of molecular sciences · 2023Article
- Pumilio protects Xbp1 mRNA from regulated Ire1-dependent decay.Nature communications · 2022Article
- Newly synthesized mRNA escapes translational repression during the acute phase of the mammalian unfolded protein response.PloS one · 2022Article
- Genome-wide mRNA profiling identifies X-box-binding protein 1 (XBP1) as an IRE1 and PUMA repressor.Cellular and molecular life sciences : CMLS · 2021Article
- The Role of PERK in Understanding Development of Neurodegenerative Diseases.International journal of molecular sciences · 2021Review
- Combined Transcriptomic and Proteomic Analysis of Perk Toxicity Pathways.International journal of molecular sciences · 2021Article
- Revealing the hidden reality of the mammalian 12-h ultradian rhythms.Cellular and molecular life sciences : CMLS · 2021Review
- GIPR Signaling in Immune Cells Maintains Metabolically Beneficial Type 2 Immune Responses in the White Fat From Obese Mice.Frontiers in immunology · 2021Article
- Protein Palmitoylation Regulates Cell Survival by Modulating XBP1 Activity in Glioblastoma Multiforme.Molecular therapy oncolytics · 2020Article
- Review
- 12-h clock regulation of genetic information flow by XBP1s.PLoS biology · 2020Article
- Herpesviruses and the Unfolded Protein Response.Viruses · 2019Review
Corrections and comments
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Authors and funding
8 authors at 5 institutions in 3 countries.
Funding
Abstract
The accumulation of unfolded proteins in the endoplasmic reticulum (ER) triggers transcriptional and translational reprogramming. This unfolded protein response (UPR) protects cells during transient stress and can lead to apoptosis during prolonged stress. Two key mediators of the UPR are PKR-like ER kinase (PERK), which phosphorylates the α subunit of eukaryotic translation initiation factor 2 (eIF2α), resulting in decreased protein synthesis, and the α subunit of inositol-requiring enzyme 1 (IRE1α), which initiates cytoplasmic splicing of the mRNA encoding the transcription factor X-box binding protein 1 (XBP1). XBP1 induces transcription of genes involved in protein quality control. This report describes cross talk between these two pathways: phosphorylation of eIF2α was required for maximal induction of spliced XBP1 (XBP1s) protein levels via a mechanism that involved stabilization of XBP1s mRNA. By using mouse embryo fibroblasts deficient in UPR signaling pathways, we demonstrate that stress-induced stabilization of XBP1s mRNA requires cytoplasmic splicing of the mRNA and inhibition of its translation. Because the XBP1s protein promotes transcription of its own gene, the UPR-induced mRNA stabilization is part of a positive feedback loop that induces XBP1s protein accumulation and transcription of target genes during stress. We propose a model in which eIF2α phosphorylation-mediated control of mRNA turnover is a molecular switch that regulates the stress response transcription program and the ER's capacity for protein folding during stress.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.