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). 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. 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.

SARS-CoV-2 Spike Protein Receptor Binding-ACE2 Interaction Increases Carbohydrate Sulfotransferases and Reduces N-Acetylgalactosamine-4-Sulfatase through Phospho-p38-MAPK and RB-E2F1

“…Other work has shown that when ARSB is inhibited and 4-sulfation sustained, SHP2 binding to chondroitin 4-sulfate is increased, leading to reduced SHP2 activity and sustained phosphorylation of ERK1,2, JNK, and p38 [14,53-56]. The impact of phospho-38-MAPK on N-terminal Rb phosphorylation, Rb-E2F1 binding, and suppression of ARSB promoter activation, may be part of a loop, in which p38 phosphorylation is sustained, due to enhanced chondroitin 4-sulfate-SHP2 binding which follows decline in ARSB and increased chondroitin 4-sulfation.…”

“…Arylsulfatase B (ARSB) activity measurements were performed using a fluorometric assay, following a standard protocol with 20 μl of homogenate and 80 μl of assay buffer (Na acetate 50mM with barium acetate 20mM, pH 5.6) with 100μl of substrate (5 mM 4-MUS in assay buffer) in a black microplate, as previously detailed [14].…”

“…CHST11 is a carbohydrate sulfotransferase that adds 4-sulfate groups to D-N-acetylgalactosamine residues which are linked to D-glucuronate by β-1,3 glycosidic bonds in chondroitin 4-sulfate or to D-iduronate in dermatan sulfate. Increases in chondroitin 4-sulfate (C4S) and dermatan sulfate follow decline in arylsulfatase B (ARSB, N-acetylgalactosamine-4-sulfatase), since ARSB is the enzyme that removes 4-sulfate groups from N-acetylgalactosamine 4-sulfate residues and is required for the degradation of C4S and dermatan sulfate, as evident by the accumulation of these sulfated glycosaminoglycans in the congenital disease Mucopolysaccharidosis VI (Maroteaux-Lamy Syndrome) caused by mutations of ARSB [13,14]. Accumulation of chondroitin sulfate is recognized as a significant factor in lung fibrosis of different etiologies [15-18], and treatment with recombinant ARSB ameliorated cardiac fibrosis in an animal model [19].…”