Abstract
Perturbations of glycosaminoglycan metabolism lead to mucopolysaccharidoses (MPS)—lysosomal storage diseases. One type of MPS (type VI) is associated with a deficiency of arylsulfatase B (ARSB), for which we previously established a cellular model using pulmonary artery endothelial cells with a silenced ARSB gene. Here, we explored the effects of silencing the ARSB gene on the growth of human pulmonary artery smooth muscle cells in the presence of different concentrations of dermatan sulfate (DS). The viability of pulmonary artery smooth muscle cells with a silenced ARSB gene was stimulated by the dermatan sulfate. In contrast, the growth of pulmonary artery endothelial cells was not affected. As shown by microarray analysis, the expression of the arylsulfatase G (ARSG) in pulmonary artery smooth muscle cells increased after silencing the arylsulfatase B gene, but the expression of genes encoding other enzymes involved in the degradation of dermatan sulfate did not. The active site of arylsulfatase G closely resembles that of arylsulfatase B, as shown by molecular modeling. Together, these results lead us to propose that arylsulfatase G can take part in DS degradation; therefore, it can affect the functioning of the cells with a silenced arylsulfatase B gene.
Highlights
Arylsulfatase catalyzes the hydrolysis of sulfate ester bonds (O-sulfatase activity) in glycosaminoglycans (GAG), sulfate esters, small aromatic molecules, and sulfolipids [1,2]
No differences that would explain these different responses to dermatan sulfate (DS) were revealed by microarray analysis of transcripts coding for enzymes involved in the degradation of DS (Table 1); for both pulmonary artery smooth muscle (PASM) and HPAEC cells treated with siARSB, we observed a change in the level of arylsulfatase B (ARSB) only
Analysis of the expression of transcripts for other members of the arylsulfatase gene family (Table 2) revealed that in PASM cells, a reduction of ARSB expression was accompanied by the upregulation of arylsulfatase G (ARSG), an effect not observed in HPAEC cells
Summary
Arylsulfatase catalyzes the hydrolysis of sulfate ester bonds (O-sulfatase activity) in glycosaminoglycans (GAG), sulfate esters, small aromatic molecules, and sulfolipids [1,2]. The human arylsulfatases family contains 11 members: A, B, C, D, E, F, G, H, I, J, and K. All family members share 20–60% amino acid homology, reflected by similarities in their active site architecture and tertiary structures. Conserved motifs are present especially in the N-terminal part of the chain containing active site residues as well as binding sites for divalent ions, which suggests a similar mechanism of action. Their activity is dependent on the presence of a cysteine posttranslationally modified to formylglycine and hydroxyformylglycine (formylglycine hydrate or a gem-diol) in the active site [7,8,9]. The differences in substrate specificity among the family members are believed to be a result of only subtle differences in active site architecture [2]
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