ArticleThe Journal of biological chemistry2019
The kinase PERK and the transcription factor ATF4 play distinct and essential roles in autophagy resulting from tunicamycin-induced ER stress.
Article in The Journal of biological chemistry, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 107 papers, 1 of them a synthesis that pooled it.
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107 citing papers in PubMed, 1 synthesis or guideline pooled it, 199 citations in OpenAlex.
- Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)Autophagy · 2021Guideline
- Ubiquitin and ubiquitin-like modifications in the endoplasmic reticulum stress response.The FEBS journal · 2026Review
- Targeting endoplasmic reticulum stress to attenuate cisplatin resistance in non-small cell lung cancer.Medical oncology (Northwood, London, England) · 2026Article
- Unfolded Protein Response Pathways in Cancer: Mechanisms, Tumor Biology and Therapeutic Opportunities.Molecular diagnosis & therapy · 2026Review
- Distinct roles of COPI proteins attenuated in cell senescence.Science advances · 2026Article
- Regulation of Myogenic Cell Apoptosis, UPS, and Autophagy During Mammalian Skeletal Myogenesis.Cells · 2026Review
- Targeting programmed cell death: a novel therapeutic paradigm for cancer based on mode-of-death classification.Apoptosis : an international journal on programmed cell death · 2026Review
- Transcriptional and epigenetic regulation of autophagy: mechanisms, disease relevance and therapeutic opportunities.Signal transduction and targeted therapy · 2026Review
- Genomic insights into the tunicamycin-induced endoplasmic reticulum stress response in peripheral blood mononuclear cells: A comprehensive RNA sequencing analysis.Biochemistry and biophysics reports · 2026Article
- Differential regulation of ZFAS1 splice variants by endoplasmic reticulum stress in hepatocyte cell lines.FEBS open bio · 2026Article
- Regulation of autophagy by the p53 family and the implications for cancer therapies.Discover oncology · 2026Review
- Discovery of Autophagy Modulators that Increase I1061T NPC1 Expression and Promote Cholesterol Efflux in Niemann-Pick Type C Patient-Derived Fibroblasts.ACS chemical biology · 2026Article
- An RNA-sequencing analysis to determine potential upstream transcriptional regulators of essential amino acid deficiency responses in bovine mammary epithelial cells.BMC genomics · 2026Article
- PERK/ATF4/LAMP3-arm contributes to the aggressive phenotype of hepatocellular carcinoma cells in response to the chronic ethanol exposure.Scientific reports · 2026Article
- ATF4 regulates mitochondrial dysfunction and mitophagy, contributing to corneal endothelial apoptosis.Scientific reports · 2026Article
- RETRACTED: Plant rhabdovirus glycoprotein activates unfolded protein response-mediated antiviral ER-phagy in insect vectors.PLoS pathogens · 2026Article
- Endoplasmic reticulum stress-mediated cell death in spinal cord injury: from molecular mechanisms to therapeutic applications.Frontiers in cell and developmental biology · 2026Review
- Unfolded protein response in bronchopulmonary dysplasia: mechanisms, pathways, and therapeutic implications.Frontiers in cell and developmental biology · 2026Review
- Combination treatment with epibrassinolide overcomes tamoxifen resistance in breast cancer cells via endoplasmic reticulum stress induction.Molecular biology reports · 2025Article
- Oncolytic virus and immunogenic cell death in cancer therapy.Tumour virus research · 2025Review
47 more citing papers are in PubMed but not listed here.
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Authors and funding
7 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Endoplasmic reticulum (ER) stress is thought to activate autophagy via unfolded protein response (UPR)-mediated transcriptional up-regulation of autophagy machinery components and modulation of microtubule-associated protein 1 light chain 3 (LC3). The upstream UPR constituents pancreatic EIF2-α kinase (PERK) and inositol-requiring enzyme 1 (IRE1) have been reported to mediate these effects, suggesting that UPR may stimulate autophagy via PERK and IRE1. However, how the UPR and its components affect autophagic activity has not been thoroughly examined. By analyzing the flux of LC3 through the autophagic pathway, as well as the sequestration and degradation of autophagic cargo, we here conclusively show that the classical ER stressor tunicamycin (TM) enhances autophagic activity in mammalian cells. PERK and its downstream factor, activating transcription factor 4 (ATF4), were crucial for this induction, but surprisingly, IRE1 constitutively suppressed autophagic activity. TM-induced autophagy required autophagy-related 13 (ATG13), Unc-51-like autophagy-activating kinases 1/2 (ULK1/ULK2), and GABA type A receptor-associated proteins (GABARAPs), but interestingly, LC3 proteins appeared to be redundant. Strikingly, ATF4 was activated independently of PERK in both LNCaP and HeLa cells, and our further examination revealed that ATF4 and PERK regulated autophagy through separate mechanisms. Specifically, whereas ATF4 controlled transcription and was essential for autophagosome formation, PERK acted in a transcription-independent manner and was required at a post-sequestration step in the autophagic pathway. In conclusion, our results indicate that TM-induced UPR activates functional autophagy, and whereas IRE1 is a negative regulator, PERK and ATF4 are required at distinct steps in the autophagic pathway.
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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.