ArticleInvestigative ophthalmology & visual science2012
Selective activation of ATF6 and PERK endoplasmic reticulum stress signaling pathways prevent mutant rhodopsin accumulation.
Article in Investigative ophthalmology & visual science, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 60 papers.
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60 citing papers in PubMed, 80 citations in OpenAlex.
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- Aggregation of the Constitutively Active K296E Rhodopsin Mutant Contributes to Retinal Degeneration.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2025Article
- Global research trends on endoplasmic reticulum stress in retinal diseases from 2000 to 2024.International ophthalmology · 2025Review
- SON-dependent nuclear speckle rehabilitation alleviates proteinopathies.bioRxiv : the preprint server for biology · 2025Article
- Propylparaben-induced endoplasmic reticulum stress triggers G2/M phase cell cycle arrest and initiates caspase-3-dependent apoptosis in human lung cells.Genes & genomics · 2025Article
- The endoplasmic reticulum: Homeostasis and crosstalk in retinal health and disease.Progress in retinal and eye research · 2024Review
- PERK prevents rhodopsin degradation during retinitis pigmentosa by inhibiting IRE1-induced autophagy.The Journal of cell biology · 2023Article
- Lysine Ubiquitylation Drives Rhodopsin Protein Turnover.Advances in experimental medicine and biology · 2023Article
- Network biology analysis of P23H rhodopsin interactome identifies protein and mRNA quality control mechanisms.Scientific reports · 2022Article
- Cellular stress signaling and the unfolded protein response in retinal degeneration: mechanisms and therapeutic implications.Molecular neurodegeneration · 2022Review
- A protein-trap allele reveals roles for Drosophila ATF4 in photoreceptor degeneration, oogenesis and wing development.Disease models & mechanisms · 2022Article
- Endoplasmic Reticulum Stress of Gut Enterocyte and Intestinal Diseases.Frontiers in molecular biosciences · 2022Review
- Involvement of endoplasmic reticulum stress in rifampicin-induced liver injury.Frontiers in pharmacology · 2022Review
- Epigenetics and endoplasmic reticulum in podocytopathy during diabetic nephropathy progression.Frontiers in immunology · 2022Review
- Neuroinflammation as a Therapeutic Target in Retinitis Pigmentosa and Quercetin as Its Potential Modulator.Pharmaceutics · 2021Review
- ATF6 is required for efficient rhodopsin clearance and retinal homeostasis in the P23H rho retinitis pigmentosa mouse model.Scientific reports · 2021Article
- Defects in Protein Folding and/or Quality Control Cause Protein Aggregation in the Endoplasmic Reticulum.Progress in molecular and subcellular biology · 2021Article
- Ginkgo Biloba Extract EGB761 Ameliorates the Extracellular Matrix Accumulation and Mesenchymal Transformation of Renal Tubules in Diabetic Kidney Disease by Inhibiting Endoplasmic Reticulum Stress.BioMed research international · 2021Article
- Review
- Calpain Activation Is the Major Cause of Cell Death in Photoreceptors Expressing a Rhodopsin Misfolding Mutation.Molecular neurobiology · 2020Article
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
purposeMany rhodopsin mutations that cause retinitis pigmentosa produce misfolded rhodopsin proteins that are retained within the endoplasmic reticulum (ER) and cause photoreceptor cell death. Activating transcription factor 6 (ATF6) and protein kinase RNA-like endoplasmic reticulum kinase (PERK) control intracellular signaling pathways that maintain ER homeostasis. The aim of this study was to investigate how ATF6 and PERK signaling affected misfolded rhodopsin in cells, which could identify new molecular therapies to treat retinal diseases associated with ER protein misfolding.
methodsTo examine the effect of ATF6 on rhodopsin, wild-type (WT) or mutant rhodopsins were expressed in cells expressing inducible human ATF6f, the transcriptional activator domain of ATF6. Induction of ATF6f synthesis rapidly activated downstream genes. To examine PERK's effect on rhodopsin, WT or mutant rhodopsins were expressed in cells expressing a genetically altered PERK protein, Fv2E-PERK. Addition of the dimerizing molecule (AP20187) rapidly activated Fv2E-PERK and downstream genes. By use of these strategies, it was examined how selective ATF6 or PERK signaling affected the fate of WT and mutant rhodopsins.
resultsATF6 significantly reduced T17M, P23H, Y178C, C185R, D190G, K296E, and S334ter rhodopsin protein levels in the cells with minimal effects on monomeric WT rhodopsin protein levels. By contrast, the PERK pathway reduced both levels of WT, mutant rhodopsins, and many other proteins in the cell.
conclusionsThis study indicates that selectively activating ATF6 or PERK prevents mutant rhodopsin from accumulating in cells. ATF6 signaling may be especially useful in treating retinal degenerative diseases arising from rhodopsin misfolding by preferentially clearing mutant rhodopsin and abnormal rhodopsin aggregates.
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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.