Profound Impact of Decline in N-Acetylgalactosamine-4-Sulfatase (Arylsulfatase B) on Molecular Pathophysiology and Human Diseases

Abstract

The enzyme N-acetylgalactosamine-4-sulfatase (Arylsulfatase B; ARSB) was originally identified as a lysosomal enzyme which was deficient in Mucopolysaccharidosis VI (MPS VI; Maroteaux-Lamy Syndrome). The newly directed attention to the impact of ARSB in human pathobiology indicates a broader, more pervasive effect, encompassing roles as a tumor suppressor, transcriptional mediator, redox switch, and regulator of intracellular and extracellular-cell signaling. By controlling the degradation of chondroitin 4-sulfate and dermatan sulfate by removal or failure to remove the 4-sulfate residue at the non-reducing end of the sulfated glycosaminoglycan chain, ARSB modifies the binding or release of critical molecules into the cell milieu. These molecules, such as galectin-3 and SHP-2, in turn, influence crucial cellular processes and events which determine cell fate. Identification of ARSB at the cell membrane and in the nucleus expands perception of the potential impact of decline in ARSB activity. The regulation of availability of sulfate from chondroitin 4-sulfate and dermatan sulfate may also affect sulfate assimilation and production of vital molecules, including glutathione and cysteine. Increased attention to ARSB in mammalian cells may help to integrate and deepen our understanding of diverse biological phenomenon and to approach human diseases with new insights.

Increased Cerebral Serum Amyloid A2 and Parameters of Oxidation in Arylsulfatase B (N-Acetylgalactosamine-4-Sulfatase)-Null Mice

“…The study findings are consistent with previous reports of GWAS data linking ARSB and increased AD [14] and of relative increase in ARSB in neurons lacking amyloid in AD brains [15]. Study data are also consistent with previous findings of increase in chondroitin sulfate proteoglycans, specifically CSPG4 [4], neurocan [12], and versican [19], and chondroitin 4-sulfate [4,12,18,19], when ARSB was silenced in human cells.…”

“…Arylsulfatase B (ARSB) measurements were performed using a fluorometric assay, following a standard protocol with 20 μl of homogenate and 80 μl of assay buffer (0.05 M Na acetate buffer with barium acetate, pH 5.6) with 100 μl of substrate [5mM 4methylumbelliferyl sulfate (MUS) in assay buffer] in a black microplate, as previously reported [1]. To verify that silencing of ARSB was not associated with generalized reduction of sulfatase activity, galactose-6-sulfatase (GALNS), arylsulfatase A (ARSA), and steroid sulfatase activities were also determined, as previously [4].…”

“…For activity, ARSB must undergo post-translational modification, which requires molecular oxygen and the formylglycine generating enzyme (FGE) [16,17]. Investigations indicated that decline in ARSB replicate the effects of hypoxia in human bronchial epithelial and intestinal epithelial cells [18], and that ARSB-mediated changes in chondroitin 4-sulfation affect critical signaling and transcriptional events [4,19], as well as the availability of vital signaling molecules [4]. These findings in different tissues indicate the importance of ARSB in the response to injury and demonstrate how decline in ARSB contributes to diverse pathophysiological mechanisms.…”

“…The rationale for these studies was based on several findings, including: 1) the association of decline in ARSB with spinal cord injury, peripheral and optic nerve injury, and traumatic brain injury [6][7][8][9][10][11][12]; 2) genetic evidence of association of ARSB with AD [14,15]; 3) previous studies of chondroitin sulfates and chondroitin sulfate proteoglycans in studies of AD [20][21][22][23][24][25][26]; and 4) changes in SAA2 expression identified in the hepatic tissue of ARSB-null mice [4], the studies were undertaken to assess whether decline in ARSB and the subsequent increase in C4S in the ARSB-null mouse were associated with parameters related toAD. Based on reports of associations with i-NOS [27,28], glutathione levels [29,30], and lipid peroxidation [31,32], measurements of inducible nitric oxide synthase (iNOS), thiol levels, and lipid peroxidation products, as well as control serum amyloid A2 in cortical and hippocampal tissue of the ARSB-null mouse are reported.…”

Increased Cerebral Serum Amyloid A2 and Parameters of Oxidation in Arylsulfatase B (N-Acetylgalactosamine-4-Sulfatase)-Null Mice

“…Arylsulfatase B (ARSB) measurements were performed using a fluorometric assay, following a standard protocol with 20μl of homogenate and 80μl of assay buffer (0.05 M Na acetate buffer with barium acetate, pH 5.6) with 100μl of substrate [5 mM 4-methylumbelliferyl sulfate (MUS) in assay buffer] in a black microplate, as previously reported [ 1 ]. To verify that silencing of ARSB was not associated with generalized reduction of sulfatase activity, galactose-6-sulfatase (GALNS), arylsulfatase A (ARSA), and steroid sulfatase activities were also determined, as previously [ 4 ].…”