Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: EC:3.4.25.1 (
proteasome
)
28,817
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
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.
...
PMID:Shutdown of ER-associated degradation pathway rescues functions of mutant iduronate 2-sulfatase linked to mucopolysaccharidosis type II. 3004 67
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.
...
PMID:Endoplasmic Reticulum and Lysosomal Quality Control of Four Nonsense Mutants of Iduronate 2-Sulfatase Linked to Hunter's Syndrome. 3189 84
