A non-conserved miRNA regulates lysosomal function and impacts on a human lysosomal storage disorder

Lisa B. Frankel, Chiara Di Malta, Jiayu Wen, Eeva-Liisa Eskelinen, Andrea Ballabio and Anders H. Lund ()
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Lisa B. Frankel: Biotech Research and Innovation Center, University of Copenhagen
Chiara Di Malta: Telethon Institute of Genetics and Medicine (TIGEM), Federico II University
Jiayu Wen: University of Copenhagen
Eeva-Liisa Eskelinen: University of Helsinki
Andrea Ballabio: Telethon Institute of Genetics and Medicine (TIGEM), Federico II University
Anders H. Lund: Biotech Research and Innovation Center, University of Copenhagen

Nature Communications, 2014, vol. 5, issue 1, 1-11

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms6840

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