Role of Arylsulfatase K (ARSK) in lysosomal function in health and disease
Final Report Abstract
The degradation of the different glycosaminoglycans (GAGs) like heparan sulfate (HS) involves a series of hydrolytic glycosidases and sulfatases that act sequentially on the nonreducing end of the saccharide chain. Enzymes have been cloned that hydrolyze all of the known linkages with the exception of the removal of the 2-O-sulfate group from 2-sulfoglucuronate, which is found in heparan sulfate and dermatan sulfate. We were able to show that arylsulfatase K is the glucuronate-2-sulfatase by using specific synthetic sulfated disaccharide substrates and demonstrated desulfation by GRIL-LC/MS analysis. Arylsulfatase K acts selectively on 2-sulfoglucuronate and thus lacks activity against the 2-O-sulfated iduronate epimer, which is the exclusive substrate for iduronate- 2-sulfatase (IDS). As arylsulfatase K has all of the properties expected of a lysosomal enzyme, we conclude that arylsulfatase K is the long sought lysosomal glucuronate-2-sulfatase (GDS). In a next approach, we established an alternative, but also specific GDS- assay, in which we labeled appropriate substrate saccharides with the fluorophore AMAC and demonstrated specific activity of GDS towards 2-sulfoglucuronate. Next, we evaluated the physiological relevance of glucuronate-2-O-desulfation by establishing and characterizing an Arsk-deficient mouse model. The complete lack of glucuronate desulfation was demonstrated by the specific AMAC-based activity assay as well as by GRIL-LC/ MS. Arsk-deficient mice show a moderate accumulation of heparan sulfate and chondroitin sulfate metabolites characterized by 2-O-sulfated glucuronate moieties at their non-reducing ends in an organ-specific manner. (Neuro)pathophysiological studies reflect a rather mild phenotype including behavioral changes. Interestingly, no prominent lysosomal storage pathology, bone abnormalities or retina degradation were detected. These results suggest that ARSK-deficient patients might suffer from a mild and late onset MPS-like phenotype.
Publications
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(2017) Arylsulfatase K is the Lysosomal 2-Sulfoglucuronate Sulfatase. ACS Chem Biol. 12(2):367-373
Dhamale OP, Lawrence R, Wiegmann EM, Shah BA, Al-Mafraji K, Lamanna WC, Lübke T, Dierks T, Boons GJ, Esko JD
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(2020) Arylsulfatase K inactivation causes mucopolysaccharidosis due to deficient glucuronate desulfation of heparan and chondroitin sulfate. Biochem J. 477(17):3433-3451
Trabszo C, Ramms B, Chopra P, Lüllmann-Rauch R, Stroobants S, Sproß J, Jeschke A, Schinke T, Boons GJ, Esko JD, Lübke T, Dierks T
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(2020) Lysosomal sulfatases – a growing family. Biochem J. 477(20):3963-3983
Lübke T & Damme M
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Novel subtype of mucopolysaccharidosis caused by arylsulfatase K (ARSK) deficiency. Journal of Medical Genetics, Vol. 59. 2022, Issue 10, pp. 957-964.
Verheyen S., Blatterer J., Speicher M.R., Bhavani G.S., Boons G.J., Ilse MB., Andrae D., Sproß J., Vaz F.M., Kircher S.G., Posch-Pertl L., Baumgartner D., Lübke T., Shah H., Al Kaissi A., Girisha K.M., Plecko B.
