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.
Acute renal failure caused by ingestion of ethylene glycol during a suicide
attempt is rare. In this case report, a Japanese man ingested ethylene glycol in a suicide
attempt and was transported to our hospital. He complained of severe nausea and blood
tests revealed metabolic acidosis, and elevated white blood cell count, creatinine and
BUN levels. Hemodialysis was implemented four hours after the ethylene glycol was
ingested, and urine volume increased to 1,500 mL/day on the ninth day after admission.
Creatinine clearance, however, did not improve. A renal biopsy performed on the 45th
day revealed numerous collapsed glomerulus, cortical infarction, and swelling of the
renal tubular epithelial cells. Hemodialysis has been recommended for the treatment of
ethylene glycol poisoning in the presence of severe metabolic acidosis that is
unresponsive to therapy.
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