Molecular characterization of arylsulfatase G: expression, processing, glycosylation, transport, and activity.
Arylsulfatase G (ARSG) is a recently identified lysosomal sulfatase that was shown to be responsible for the degradation of 3-O-sulfated N-sulfoglucosamine residues of heparan sulfate glycosaminoglycans. Deficiency of ARSG leads to a new type of mucopolysaccharidosis, as described in a mouse model. Here, we provide a detailed molecular characterization of the endogenous murine enzyme. ARSG is expressed and proteolytically processed in a tissue-specific manner. The 63-kDa single-chain precursor protein localizes to pre-lysosomal compartments and tightly associates with organelle membranes, most likely the endoplasmic reticulum. In contrast, proteolytically processed ARSG fragments of 34-, 18-, and 10-kDa were found in lysosomal fractions and lost their membrane association. The processing sites and a disulfide bridge between the 18- and 10-kDa chains could be roughly mapped. Proteases participating in the processing were identified as cathepsins B and L. Proteolytic processing is dispensable for hydrolytic sulfatase activity in vitro. Lysosomal transport of ARSG in the liver is independent of mannose 6-phosphate, sortilin, and Limp2. However, mutation of glycosylation site N-497 abrogates transport of ARSG to lysosomes in human fibrosarcoma cells, due to impaired mannose 6-phosphate modification.
['Kowalewski|Björn|B|', 'Lübke|Torben|T|', 'Kollmann|Katrin|K|', 'Braulke|Thomas|T|', 'Reinheckel|Thomas|T|', 'Dierks|Thomas|T|', 'Damme|Markus|M|']
D020816:Amino Acid Motifs D000818:Animals D001192:Arylsulfatases D006031:Glycosylation D006801:Humans D008247:Lysosomes D051379:Mice D018345:Mice, Knockout D010447:Peptide Hydrolases D011498:Protein Precursors D011499:Protein Processing, Post-Translational D021381:Protein Transport
Arylsulfatase G Lysosome Sulfatase Heparan Sulfate Mucopolysaccharidosis Proteolytic Processing Mannose 6-Phosphate Enzyme Processing Lysosomal Glycoprotein Lysosomal Storage Disease