Hypoxia Reduces Arylsulfatase B Activity and Silencing Arylsulfatase B Replicates and Mediates the Effects of Hypoxia
نویسندگان
چکیده
This report presents evidence of 1) a role for arylsulfatase B (ARSB; N-acetylgalactosamine-4-sulfatase) in mediating intracellular oxygen signaling; 2) replication between the effects of ARSB silencing and hypoxia on sulfated glycosaminoglycan content, cellular redox status, and expression of hypoxia-associated genes; and 3) a mechanism whereby changes in chondroitin-4-sulfation that follow either hypoxia or ARSB silencing can induce transcriptional changes through galectin-3. ARSB removes 4-sulfate groups from the non-reducing end of chondroitin-4-sulfate and dermatan sulfate and is required for their degradation. For activity, ARSB requires modification of a critical cysteine residue by the formylglycine generating enzyme and by molecular oxygen. When primary human bronchial and human colonic epithelial cells were exposed to 10% O(2) × 1 h, ARSB activity declined by ~41% and ~30% from baseline, as nuclear hypoxia inducible factor (HIF)-1α increased by ~53% and ~37%. When ARSB was silenced, nuclear HIF-1α increased by ~81% and ~61% from baseline, and mRNA expression increased to 3.73 (± 0.34) times baseline. Inversely, ARSB overexpression reduced nuclear HIF-1α by ~37% and ~54% from baseline in the epithelial cells. Hypoxia, like ARSB silencing, significantly increased the total cellular sulfated glycosaminoglycans and chondroitin-4-sulfate (C4S) content. Both hypoxia and ARSB silencing had similar effects on the cellular redox status and on mRNA expression of hypoxia-associated genes. Transcriptional effects of both ARSB silencing and hypoxia may be mediated by reduction in galectin-3 binding to more highly sulfated C4S, since the galectin-3 that co-immunoprecipitated with C4S declined and the nuclear galectin-3 increased following ARSB knockdown and hypoxia.
منابع مشابه
Identification of a Novel Arylsulfatase B Gene Mutation in Three Unrelated Iranian Mucopolysaccharidosis Type-VI Patients with Different Phenotype Severity
Background: Mucopolysaccharidosis type-VI (MPS-VI), which is inherited as an autosomal recessive trait, results from the deficiency of N-acetylgalactosamine 4-sulfatase (arylsulfatase B) activity and the lysosomal accumulation of dermatan sulfate. In this study, ARSB mutation analysis was performed on three unrelated patients who were originally from the West Azerbaijan province of Iran. Method...
متن کاملRestriction of Aerobic Metabolism by Acquired or Innate Arylsulfatase B Deficiency: A New Approach to the Warburg Effect
Aerobic respiration is required for optimal efficiency of metabolism in mammalian cells. Under circumstances when oxygen utilization is impaired, cells survive by anerobic metabolism. The malignant cell has cultivated the use of anerobic metabolism in an aerobic environment, the Warburg effect, but the explanation for this preference is not clear. This paper presents evidence that deficiency of...
متن کاملMutational analysis of ARSB gene in mucopolysaccharidosis type VI: identification of three novel mutations in Iranian patients
Objective(s): Mucopolysaccharidosis VI (MPS VI) or Maroteaux-Lamy syndrome is a rare metabolic disorder, resulting from the deficient activity of the lysosomal enzyme arylsulfatase B (ARSB). The enzymatic defect of ARSB leads to progressive lysosomal storage disorder and accumulation of glycosaminoglycan (GAG) dermatan sulfate (DS), which causes harmful effects on various organs and tissues an...
متن کاملGenetics of murine liver and kidney arysulfatase b.
Mice from 12 inbred strains were surveyed for variation of kidney and liver arylsulfatase levels. Kidney variation was due to differences in the activity of arylsulfatase B. Twofold higher activities of arylsulfatase B in SWR/J kidney compared to A/HeJ kidney were determined by an autosomal gene which may be identical to the structural gene for arylsulfatase B since the SWR/J enzyme was more he...
متن کاملDelayed posthypoxic demyelination
Article abstract-Delayed demyelination is a rare and poorly understood complication of hypoxic brain injury. A previous case report has suggested an association with mild-to-moderate deficiency of arylsulfatase A. We describe a 36-year-old man who recovered completely from an episode of hypoxia related to drug overdose, and 2 weeks later progressed from a confusional state to deep coma. MRI sho...
متن کامل