Targeting defective sphingosine kinase 1 in Niemann-Pick type C disease with an activator mitigates cholesterol accumulation.

Autor:	Newton J; Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA. Electronic address: newtonjc2@vcu.edu., Palladino END; Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA., Weigel C; Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA., Maceyka M; Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA., Gräler MH; Department of Anesthesiology and Intensive Care Medicine, Center for Sepsis Control and Care (CSCC), and Center for Molecular Biomedicine (CMB), University Hospital Jena, Jena, Germany., Senkal CE; Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA., Enriz RD; Facultad de Quimica, Bioquimica, y Farmacia, Universidad Nacional de San Luis, Instituto Multidisciplinario de Investigaciones Biológicas (IMIBIO-CONICET), San Luis, Argentina., Marvanova P; Department of Chemical Drugs, Faculty of Pharmacy, University of Veterinary and Pharmaceutical Sciences, Brno, Czech Republic., Jampilek J; Department of Analytical Chemistry, Faculty of Natural Sciences, Comenius University, Bratislava, Slovakia., Lima S; Department of Biology, Virginia Commonwealth University, Richmond, Virginia, USA., Milstien S; Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA., Spiegel S; Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA. Electronic address: sarah.spiegel@vcuhealth.org.
Jazyk:	angličtina
Zdroj:	The Journal of biological chemistry [J Biol Chem] 2020 Jul 03; Vol. 295 (27), pp. 9121-9133. Date of Electronic Publication: 2020 May 08.
DOI:	10.1074/jbc.RA120.012659
Abstrakt:	Niemann-Pick type C (NPC) disease is a lysosomal storage disorder arising from mutations in the cholesterol-trafficking protein NPC1 (95%) or NPC2 (5%). These mutations result in accumulation of low-density lipoprotein-derived cholesterol in late endosomes/lysosomes, disruption of endocytic trafficking, and stalled autophagic flux. Additionally, NPC disease results in sphingolipid accumulation, yet it is unique among the sphingolipidoses because of the absence of mutations in the enzymes responsible for sphingolipid degradation. In this work, we examined the cause for sphingosine and sphingolipid accumulation in multiple cellular models of NPC disease and observed that the activity of sphingosine kinase 1 (SphK1), one of the two isoenzymes that phosphorylate sphingoid bases, was markedly reduced in both NPC1 mutant and NPC1 knockout cells. Conversely, SphK1 inhibition with the isotype-specific inhibitor SK1-I in WT cells induced accumulation of cholesterol and reduced cholesterol esterification. Of note, a novel SphK1 activator (SK1-A) that we have characterized decreased sphingoid base and complex sphingolipid accumulation and ameliorated autophagic defects in both NPC1 mutant and NPC1 knockout cells. Remarkably, in these cells, SK1-A also reduced cholesterol accumulation and increased cholesterol ester formation. Our results indicate that a SphK1 activator rescues aberrant cholesterol and sphingolipid storage and trafficking in NPC1 mutant cells. These observations highlight a previously unknown link between SphK1 activity, NPC1, and cholesterol trafficking and metabolism. Competing Interests: Conflict of interest—The authors declare that they have no conflicts of interest with the contents of this article. (© 2020 Newton et al.)
Databáze:	MEDLINE
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