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Endoplasmic Reticulum and Lysosomal Quality Control of Four Nonsense Mutants of Iduronate 2-Sulfatase Linked to Hunter's Syndrome


Marazza, Alessandro; Galli, Carmela; Fasana, Elisa; Sgrignani, Jacopo; Burda, Patricie; Fassi, Enrico M A; Baumgartner, Matthias; Cavalli, Andrea; Molinari, Maurizio (2020). Endoplasmic Reticulum and Lysosomal Quality Control of Four Nonsense Mutants of Iduronate 2-Sulfatase Linked to Hunter's Syndrome. DNA and cell biology, 39(2):226-234.

Abstract

Hunter's syndrome (mucopolysaccharidosis type II) is a rare X-linked lysosomal storage disorder caused by mutations in the iduronate-2-sulfatase (IDS) gene. Motivated by the case of a child affected by this syndrome, we compared the intracellular fate of wild-type IDS (IDS$_{WT}$) and four nonsense mutations of IDS (IDS$_{L482X}$, IDS$_{Y452X}$, IDS$_{R443X}$, and IDS$_{W337X}$) generating progressively shorter forms of IDS associated with mild to severe forms of the disease. Our analyses revealed formylation of all forms of IDS at cysteine 84, which is a prerequisite for enzymatic activity. After formylation, IDS$_{WT}$ was transported within lysosomes, where it was processed in the mature form of the enzyme. The length of disease-causing deletions correlated with gravity of the folding and transport phenotype, which was anticipated by molecular dynamics analyses. The shortest form of IDS, IDS$_{W337X}$, was retained in the endoplasmic reticulum (ER) and degraded by the ubiquitin-proteasome system. IDS$_{R443X}$, IDS$_{Y452X}$, and IDS$_{L482X}$ passed ER quality control and were transported to the lysosomes, but failed lysosomal quality control, resulting in their rapid clearance and in loss-of-function phenotype. Failure of ER quality control inspection is an established cause of loss of function observed in protein misfolding diseases. Our data reveal that fulfillment of ER requirements might not be sufficient, highlight lysosomal quality control as the distal station to control lysosomal enzymes fitness and pave the way for alternative therapeutic interventions.

Abstract

Hunter's syndrome (mucopolysaccharidosis type II) is a rare X-linked lysosomal storage disorder caused by mutations in the iduronate-2-sulfatase (IDS) gene. Motivated by the case of a child affected by this syndrome, we compared the intracellular fate of wild-type IDS (IDS$_{WT}$) and four nonsense mutations of IDS (IDS$_{L482X}$, IDS$_{Y452X}$, IDS$_{R443X}$, and IDS$_{W337X}$) generating progressively shorter forms of IDS associated with mild to severe forms of the disease. Our analyses revealed formylation of all forms of IDS at cysteine 84, which is a prerequisite for enzymatic activity. After formylation, IDS$_{WT}$ was transported within lysosomes, where it was processed in the mature form of the enzyme. The length of disease-causing deletions correlated with gravity of the folding and transport phenotype, which was anticipated by molecular dynamics analyses. The shortest form of IDS, IDS$_{W337X}$, was retained in the endoplasmic reticulum (ER) and degraded by the ubiquitin-proteasome system. IDS$_{R443X}$, IDS$_{Y452X}$, and IDS$_{L482X}$ passed ER quality control and were transported to the lysosomes, but failed lysosomal quality control, resulting in their rapid clearance and in loss-of-function phenotype. Failure of ER quality control inspection is an established cause of loss of function observed in protein misfolding diseases. Our data reveal that fulfillment of ER requirements might not be sufficient, highlight lysosomal quality control as the distal station to control lysosomal enzymes fitness and pave the way for alternative therapeutic interventions.

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Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Children's Hospital Zurich > Medical Clinic
Dewey Decimal Classification:610 Medicine & health
Scopus Subject Areas:Life Sciences > Molecular Biology
Life Sciences > Genetics
Life Sciences > Cell Biology
Language:English
Date:1 February 2020
Deposited On:04 Feb 2020 13:16
Last Modified:29 Jul 2020 13:55
Publisher:Mary Ann Liebert
ISSN:1044-5498
OA Status:Closed
Publisher DOI:https://doi.org/10.1089/dna.2019.5221
PubMed ID:31895584

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