ArticleMolecular neurobiology2016
ENC1 Modulates the Aggregation and Neurotoxicity of Mutant Huntingtin Through p62 Under ER Stress.
Article in Molecular neurobiology, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 32 citations in OpenAlex.
- The emerging role of ectodermal neural cortex 1 in cancer.Scientific reports · 2024Review
- Dual roles of UPRJournal of molecular medicine (Berlin, Germany) · 2023Review
- 4-PBA inhibits endoplasmic reticulum stress to improve autophagic flux in the treatment of protamine/lipopolysaccharide-induced interstitial cystitis in rats.Scientific reports · 2023Article
- miR-18a-5p shuttled by mesenchymal stem cell-derived extracellular vesicles alleviates early brain injury following subarachnoid hemorrhage through blockade of the ENC1/p62 axis.Cell and tissue research · 2023Article
- Regulation of Cell Proliferation and Nrf2-Mediated Antioxidant Defense: Conservation of Keap1 Cysteines and Nrf2 Binding Site in the Context of the Evolution of KLHL Family.Life (Basel, Switzerland) · 2023Article
- Upregulated ENC1 predicts unfavorable prognosis and correlates with immune infiltration in endometrial cancer.Frontiers in cell and developmental biology · 2022Article
- Mutant Huntingtin Protein Interaction Map Implicates Dysregulation of Multiple Cellular Pathways in Neurodegeneration of Huntington's Disease.Journal of Huntington's disease · 2022Article
- Ectodermal‑neural cortex 1 affects the biological function of lung cancer through the MAPK pathway.International journal of molecular medicine · 2021Article
- Control of craniofacial and brain development by Cullin3-RING ubiquitin ligases: Lessons from human disease genetics.Experimental cell research · 2020Review
- Ectodermal-neural cortex 1 as a novel biomarker predicts poor prognosis and induces metastasis in breast cancer by promoting Wnt/β-catenin pathway.Journal of cellular and molecular medicine · 2020Article
- The PERK-Dependent Molecular Mechanisms as a Novel Therapeutic Target for Neurodegenerative Diseases.International journal of molecular sciences · 2020Review
- Long Non-coding RNA MIAT Knockdown Prevents the Formation of Intracranial Aneurysm by Downregulating ENC1 via MYC.Frontiers in physiology · 2020Article
- SQSTM1/p62: A Potential Target for Neurodegenerative Disease.ACS chemical neuroscience · 2019Review
- Melatonin protects vertebral endplate chondrocytes against apoptosis and calcification via the Sirt1-autophagy pathway.Journal of cellular and molecular medicine · 2019Article
- Protein Misfolding and ER Stress in Huntington's Disease.Frontiers in molecular biosciences · 2019Review
- Filamentous Aggregation of Sequestosome-1/p62 in Brain Neurons and Neuroepithelial Cells upon Tyr-Cre-Mediated Deletion of the Autophagy Gene Atg7.Molecular neurobiology · 2018Article
- From autophagy to mitophagy: the roles of P62 in neurodegenerative diseases.Journal of bioenergetics and biomembranes · 2017Review
- Protein homeostasis of a metastable subproteome associated with Alzheimer's disease.Proceedings of the National Academy of Sciences of the United States of America · 2017Article
- Identification of genes associated with dissociation of cognitive performance and neuropathological burden: Multistep analysis of genetic, epigenetic, and transcriptional data.PLoS medicine · 2017Article
- Entanglement of UPRFrontiers in aging neuroscience · 2017Review
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Authors and funding
8 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Huntington's disease (HD) is a devastating neurodegenerative disorder, which is caused by the expression and aggregation of polyQ-expanded mutant huntingtin protein (mtHTT). While toxic mtHTT aggregates are primarily eliminated through autophagy, autophagy dysfunction is often observed in HD pathogenesis. Here, we show that ectodermal-neural cortex 1 (ENC1), a novel binding partner of sequestosome 1 (p62), negatively regulates autophagy under endoplasmic reticulum (ER) stress. We found that ER stress significantly increases the expression of ENC1 via inositol-requiring enzyme 1 (IRE1)-TNF receptor-associated factor 2 (TRAF2)-c-Jun N-terminal kinase (JNK) pathway. Ectopic expression of ENC1 alone induces the accumulation of detergent-resistant mtHTT aggregates and downregulation of ENC1 alleviates ER stress-induced mtHTT aggregation. Simultaneously, ER stress-induced impairment of autophagy flux is ameliorated by downregulation of ENC1. From immunoprecipitation and immunocytochemical assays, we found that ENC1 binds to p62 through its BTB and C-terminal Kelch (BACK) domain and this interaction is enhanced under ER stress. In particular, ENC1 preferentially interacts with the phosphorylated p62 at Ser403 during ER stress. Interestingly, ENC1 colocalizes with mtHTT aggregates and its C-terminal Kelch domain is required for interfering with the access of p62 to ubiquitinated mtHTT aggregates, thus inhibiting cargo recognition of p62. Accordingly, knockdown of ENC1 expression enhances colocalization of p62 with mtHTT aggregates. Consequently, ENC1 knockdown relieves death of neuronal cells expressing mtHTT under ER stress. These results suggest that ENC1 interacts with the phosphorylated p62 to impair autophagic degradation of mtHTT aggregates and affects cargo recognition failure under ER stress, leading to the accumulation and neurotoxicity of mtHTT 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.