ArticleThe Journal of biological chemistry2014
Endoplasmic reticulum-associated degradation of Niemann-Pick C1: evidence for the role of heat shock proteins and identification of lysine residues that accept ubiquitin.
Article in The Journal of biological chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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Who cites it
31 citing papers in PubMed, 68 citations in OpenAlex.
- Efficacy and safety of arimoclomol in Niemann-Pick disease type C: Results from a double-blind, randomised, placebo-controlled, multinational phase 2/3 trial of a novel treatment.Journal of inherited metabolic disease · 2021Trial
- NPC1 trafficking via VPS41-dependent LAMP carriers regulates endosomal cholesterol homeostasis.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Exploration of Bromodomain Proteins as Drug Targets for Niemann-Pick Type C Disease.International journal of molecular sciences · 2025Article
- Unifying biology of neurodegeneration in lysosomal storage diseases.Journal of inherited metabolic disease · 2025Review
- Mutant induced neurons and humanized mice enable identification of Niemann-Pick type C1 proteostatic therapies.JCI insight · 2024Article
- Presenilin Deficiency Results in Cellular Cholesterol Accumulation by Impairment of Protein Glycosylation and NPC1 Function.International journal of molecular sciences · 2024Article
- Chaperone-assisted E3 ligase CHIP: A double agent in cancer.Genes & diseases · 2022Review
- Chemical Regulation of the Protein Quality Control E3 Ubiquitin Ligase C-Terminus of Hsc70 Interacting Protein (CHIP).Chembiochem : a European journal of chemical biology · 2022Article
- Histatin-1 is an endogenous ligand of the sigma-2 receptor.The FEBS journal · 2021Article
- Treatment trials in Niemann-Pick type C disease.Metabolic brain disease · 2021Review
- Understanding and Treating Niemann-Pick Type C Disease: Models Matter.International journal of molecular sciences · 2020Review
- Clinical disease progression and biomarkers in Niemann-Pick disease type C: a prospective cohort study.Orphanet journal of rare diseases · 2020Observational
- NPC1 silent variant induces skipping of exon 11 (p.V562V) and unfolded protein response was found in a specific Niemann-Pick type C patient.Molecular genetics & genomic medicine · 2020Article
- Proteostasis regulators modulate proteasomal activity and gene expression to attenuate multiple phenotypes in Fabry disease.The Biochemical journal · 2020Article
- Individualized management of genetic diversity in Niemann-Pick C1 through modulation of the Hsp70 chaperone system.Human molecular genetics · 2020Article
- Image-based screen capturing misfolding status of Niemann-Pick type C1 identifies potential candidates for chaperone drugs.PloS one · 2020Article
- Modeling Niemann-Pick disease type C in a human haploid cell line allows for patient variant characterization and clinical interpretation.Genome research · 2019Article
- Quantitating the epigenetic transformation contributing to cholesterol homeostasis using Gaussian process.Nature communications · 2019Article
- NPC1 enables cholesterol mobilization during long-term potentiation that can be restored in Niemann-Pick disease type C by CYP46A1 activation.EMBO reports · 2019Article
- HSP70 induces liver X receptor pathway activation and cholesterol reduction in vitro and in vivo.Molecular metabolism · 2019Article
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Most cases with Niemann-Pick disease type C carry mutations in NPC1. Some of the mutations, including the most frequent I1061T, give rise to unstable proteins selected for endoplasmic reticulum-associated degradation. The purpose of the current study was to shed mechanistic insights into the degradation process. A proteasome inhibitor MG132 prolonged the life span of the wild-type NPC1 expressed in COS cells. The expressed protein associated with multiple chaperones including heat shock protein 90 (Hsp90), Hsp70, heat shock cognate protein 70 (Hsc70), and calnexin. Accordingly, expression of an E3 ligase CHIP (carboxyl terminus of Hsp70-interacting protein) enhanced MG132-induced accumulation of ubiquitylated NPC1. Co-expression and RNAi knockdown experiments in HEK cells indicated that Hsp70/Hsp90 stabilized NPC1, whereas Hsc70 destabilized it. In human fibroblasts carrying the I1061T mutation, adenovirus-mediated expression of Hsp70 or treatment with an HSP-inducer geranylgeranylacetone (GGA) increased the level of the mutant protein. In GGA-treated cells, the rescued protein was localized in the late endosome and ameliorated cholesterol accumulation. MALDI-TOF mass spectrometry revealed three lysine residues at amino acids 318, 792, and 1180 as potential ubiquitin-conjugation sites. Substitutions of the three residues with alanine yielded a mutant protein with a steady-state level more than three times higher than that of the wild-type. Introduction of the same substitutions to the I1061T mutant resulted in an increase in its protein level and functional restoration. These findings indicated the role of HSPs in quality control of NPC1 and revealed the role of three lysine residues as ubiquitin-conjugation sites.
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