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), pp. 226-234. Liebert 10.1089/dna.2019.5221

Text dna.2019.5221.pdf - Published Version Restricted to registered users only Available under License Publisher holds Copyright. Download (862kB)

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 (IDSWT) and four nonsense mutations of IDS (IDSL482X, IDSY452X, IDSR443X, and IDSW337X) 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, IDSWT 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, IDSW337X, was retained in the endoplasmic reticulum (ER) and degraded by the ubiquitin-proteasome system. IDSR443X, IDSY452X, and IDSL482X 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.

Interest & Impact

Downloads

2 since deposited on 24 Jan 2020
0 in the past 12 months

Citations

5 Citations in Web of Science ®
6 Citations in Scopus

Search

in Google Scholar™

Services

Actions (login required)

Edit item

Actions (login required)

Edit item