ArticleCell death & disease2018
Shutdown of ER-associated degradation pathway rescues functions of mutant iduronate 2-sulfatase linked to mucopolysaccharidosis type II.
Article in Cell death & disease, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 24 citations in OpenAlex.
- RNF13 is a previously undescribed interactor of iduronate 2-sulfatase that modifies its glycosylation and maturation.The FEBS journal · 2026Article
- Advances in Therapies for Mucopolysaccharidoses.Current issues in molecular biology · 2026Review
- Vesicular Transport Mediated by Endoplasmic Reticulum Stress Sensor BBF2H7 Orchestrates Melanin Production During Melanogenesis.International journal of molecular sciences · 2026Article
- Unifying biology of neurodegeneration in lysosomal storage diseases.Journal of inherited metabolic disease · 2025Review
- Mechanistic Insights into Dibasic Iminosugars as pH-Selective Pharmacological Chaperones to Stabilize Human α-Galactosidase.JACS Au · 2024Article
- ER-associated degradation in cystinosis pathogenesis and the prospects of precision medicine.The Journal of clinical investigation · 2023Article
- Decreased Levels of Chaperones in Mucopolysaccharidoses and Their Elevation as a Putative Auxiliary Therapeutic Approach.Pharmaceutics · 2023Article
- Mucopolysaccharidoses: Cellular Consequences of Glycosaminoglycans Accumulation and Potential Targets.International journal of molecular sciences · 2022Review
- Article
- Golgi requires a new casting in the screenplay of mucopolysaccharidosis II cytopathology.Biologia futura · 2022Review
- Hsp40s play distinct roles during the initial stages of apolipoprotein B biogenesis.Molecular biology of the cell · 2022Article
- Loss of Function of Mutant IDS Due to Endoplasmic Reticulum-Associated Degradation: New Therapeutic Opportunities for Mucopolysaccharidosis Type II.International journal of molecular sciences · 2021Review
- Mucopolysaccharidosis Type II: One Hundred Years of Research, Diagnosis, and Treatment.International journal of molecular sciences · 2020Review
- Proteasome Composition and Activity Changes in Cultured Fibroblasts Derived From Mucopolysaccharidoses Patients and Their Modulation by Genistein.Frontiers in cell and developmental biology · 2020Article
Corrections and comments
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Authors and funding
11 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Mucopolysaccharidosis type II (MPS II), also known as Hunter syndrome, is a devastating progressive disease caused by mutations in the iduronate 2-sulfatase (IDS) gene. IDS is one of the sulfatase enzymes required for lysosomal degradation of glycosaminoglycans. Mutant proteins linked to diseases are often prone to misfolding. These misfolded proteins accumulate in the endoplasmic reticulum (ER) and are degraded by the ubiquitin-proteasome pathway (ER-associated degradation (ERAD)). The decreased enzyme activities of IDS mutants may be due to accelerated degradation by ERAD. However, intracellular dynamics including degradation of IDS mutants is unexplored. In this report, we examined biochemical and biological characteristics of wild-type (WT) IDS and IDS mutants expressed in HeLa cells. IDS was shown to be glycosylated in the ER and Golgi apparatus and proteolytically cleaved to generate the mature forms in the Golgi apparatus. The mature WT IDS was translocated to the lysosome. In contrast, all IDS mutants we examined were found to accumulate in the ER and could not efficiently translocate to the lysosome. Accumulated IDS mutants in the ER were ubiquitinated by ERAD-related ubiquitin E3 ligase HRD1 followed by degradation via ERAD. Suppressed degradation of 'attenuated' mutant A85T IDS (the late-onset form of MPS II) by inhibiting ERAD components improved translocation to the lysosome and its activities. Our novel findings provide alternative targets to current principal therapies for MPS II. These perspectives provide a potenti al framework to develop fundamental therapeutic strategies and agents.
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