title: A non-conserved miRNA regulates lysosomal function and impacts on a human lysosomal storage disorder.
abstract: Sulfatases are key enzymatic regulators of sulfate homeostasis with several biological functions including degradation of glycosaminoglycans (GAGs) and other macromolecules in lysosomes. In a severe lysosomal storage disorder, multiple sulfatase deficiency (MSD), global sulfatase activity is deficient due to mutations in the sulfatase-modifying factor 1 (SUMF1) gene, encoding the essential activator of all sulfatases. We identify a novel regulatory layer of sulfate metabolism mediated by a microRNA. miR-95 depletes SUMF1 protein levels and suppresses sulfatase activity, causing the disruption of proteoglycan catabolism and lysosomal function. This blocks autophagy-mediated degradation, causing cytoplasmic accumulation of autophagosomes and autophagic substrates. By targeting miR-95 in cells from MSD patients, we can effectively increase residual SUMF1 expression, allowing for reactivation of sulfatase activity and increased clearance of sulfated GAGs. The identification of this regulatory mechanism opens the opportunity for a unique therapeutic approach in MSD patients where the need for exogenous enzyme replacement is circumvented.
authors.affiliation: Biotech Research and Innovation Center, University of Copenhagen, 2200 Copenhagen, Denmark.
authors.forename: Lisa B
authors.initials: LB
authors.lastname: Frankel
authors.affiliation: Telethon Institute of Genetics and Medicine (TIGEM), Federico II University, 80078 Naples, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Di Malta
authors.affiliation: Department of Biology, University of Copenhagen, 2200 Copenhagen, Denmark.
authors.forename: Jiayu
authors.initials: J
authors.lastname: Wen
authors.affiliation: Department of Biosciences, Division of Biochemistry and Biotechnology, University of Helsinki, 00014 Helsinki, Finland.
authors.forename: Eeva-Liisa
authors.initials: EL
authors.lastname: Eskelinen
authors.affiliation: Telethon Institute of Genetics and Medicine (TIGEM), Federico II University, 80078 Naples, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Ballabio
authors.affiliation: Biotech Research and Innovation Center, University of Copenhagen, 2200 Copenhagen, Denmark.
authors.forename: Anders H
authors.initials: AH
authors.lastname: Lund
mesh_terms: D001343:Autophagy; D006025:Glycosaminoglycans / Q000378:metabolism; D006801:Humans; D008247:Lysosomes / Q000201:enzymology / Q000378:metabolism*; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D052517:Multiple Sulfatase Deficiency Disease / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D050862:Oxidoreductases Acting on Sulfur Group Donors; D013429:Sulfatases / Q000235:genetics / Q000378:metabolism; D013431:Sulfates / Q000378:metabolism*
chemical_list: D006025:Glycosaminoglycans; C575854:MIRN95 microRNA, human; D035683:MicroRNAs; D013431:Sulfates; D050862:Oxidoreductases Acting on Sulfur Group Donors; C480483:SUMF1 protein, human; D013429:Sulfatases