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

Autores
Newton, Jason; Palladino, Elisa N.D.; Weigel, Cynthia; Maceyka, Michael; Gräler, Markus H.; Senkal, Can E.; Enriz, Ricardo Daniel; Marvanova, Pavlina; Jampilek, Josef; Lima, Santiago; Milstien, Sheldon; Spiegel, Sarah
Año de publicación
2020
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
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.
Fil: Newton, Jason. Virginia Commonwealth University School of Medicine; Estados Unidos
Fil: Palladino, Elisa N.D.. Virginia Commonwealth University School of Medicine; Estados Unidos
Fil: Weigel, Cynthia. Virginia Commonwealth University School of Medicine; Estados Unidos
Fil: Maceyka, Michael. Virginia Commonwealth University School of Medicine; Estados Unidos
Fil: Gräler, Markus H.. Universitätsklinikum Jena; Alemania
Fil: Senkal, Can E.. Virginia Commonwealth University School of Medicine; Estados Unidos
Fil: Enriz, Ricardo Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina
Fil: Marvanova, Pavlina. Veterinární univerzita Brno; República Checa
Fil: Jampilek, Josef. Univerzita Komenského v Bratislave; Eslovaquia
Fil: Lima, Santiago. Virginia Commonwealth University; Estados Unidos
Fil: Milstien, Sheldon. Virginia Commonwealth University School of Medicine; Estados Unidos
Fil: Spiegel, Sarah. Virginia Commonwealth University School of Medicine; Estados Unidos
Materia
CHOLESTEROL
GENETIC DISORDER
LIPID METABOLISM
LYSOSOMAL STORAGE DISEASE
NEURODEGENERATION
NIEMANN–PICK TYPE C
NPC1
SPHINGOLIPID
SPHINGOLIPIDS
SPHINGOSINE KINASE
SPHINGOSINE KINASE (SPHK)
SPHINGOSINE-1-PHOSPHATE (S1P)
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/136433
Acceder
id CONICETDig_9877a49e4c902f28e1c734ab61aea163
oai_identifier_str oai:ri.conicet.gov.ar:11336/136433
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Targeting defective sphingosine kinase 1 in Niemann–Pick type C disease with an activator mitigates cholesterol accumulationNewton, JasonPalladino, Elisa N.D.Weigel, CynthiaMaceyka, MichaelGräler, Markus H.Senkal, Can E.Enriz, Ricardo DanielMarvanova, PavlinaJampilek, JosefLima, SantiagoMilstien, SheldonSpiegel, SarahCHOLESTEROLGENETIC DISORDERLIPID METABOLISMLYSOSOMAL STORAGE DISEASENEURODEGENERATIONNIEMANN–PICK TYPE CNPC1SPHINGOLIPIDSPHINGOLIPIDSSPHINGOSINE KINASESPHINGOSINE KINASE (SPHK)SPHINGOSINE-1-PHOSPHATE (S1P)https://purl.org/becyt/ford/1.4https://purl.org/becyt/ford/1Niemann–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.Fil: Newton, Jason. Virginia Commonwealth University School of Medicine; Estados UnidosFil: Palladino, Elisa N.D.. Virginia Commonwealth University School of Medicine; Estados UnidosFil: Weigel, Cynthia. Virginia Commonwealth University School of Medicine; Estados UnidosFil: Maceyka, Michael. Virginia Commonwealth University School of Medicine; Estados UnidosFil: Gräler, Markus H.. Universitätsklinikum Jena; AlemaniaFil: Senkal, Can E.. Virginia Commonwealth University School of Medicine; Estados UnidosFil: Enriz, Ricardo Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; ArgentinaFil: Marvanova, Pavlina. Veterinární univerzita Brno; República ChecaFil: Jampilek, Josef. Univerzita Komenského v Bratislave; EslovaquiaFil: Lima, Santiago. Virginia Commonwealth University; Estados UnidosFil: Milstien, Sheldon. Virginia Commonwealth University School of Medicine; Estados UnidosFil: Spiegel, Sarah. Virginia Commonwealth University School of Medicine; Estados UnidosAmerican Society for Biochemistry and Molecular Biology2020-07info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/136433Newton, Jason; Palladino, Elisa N.D.; Weigel, Cynthia; Maceyka, Michael; Gräler, Markus H.; et al.; Targeting defective sphingosine kinase 1 in Niemann–Pick type C disease with an activator mitigates cholesterol accumulation; American Society for Biochemistry and Molecular Biology; Journal of Biological Chemistry (online); 295; 27; 7-2020; 9121-91340021-92581083-351XCONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1074/jbc.RA120.012659info:eu-repo/semantics/altIdentifier/url/https://www.jbc.org/article/S0021-9258(17)50333-6/fulltextinfo:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-10T13:15:45Zoai:ri.conicet.gov.ar:11336/136433instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-10 13:15:46.048CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Targeting defective sphingosine kinase 1 in Niemann–Pick type C disease with an activator mitigates cholesterol accumulation
title Targeting defective sphingosine kinase 1 in Niemann–Pick type C disease with an activator mitigates cholesterol accumulation
spellingShingle Targeting defective sphingosine kinase 1 in Niemann–Pick type C disease with an activator mitigates cholesterol accumulation
Newton, Jason
CHOLESTEROL
GENETIC DISORDER
LIPID METABOLISM
LYSOSOMAL STORAGE DISEASE
NEURODEGENERATION
NIEMANN–PICK TYPE C
NPC1
SPHINGOLIPID
SPHINGOLIPIDS
SPHINGOSINE KINASE
SPHINGOSINE KINASE (SPHK)
SPHINGOSINE-1-PHOSPHATE (S1P)
title_short Targeting defective sphingosine kinase 1 in Niemann–Pick type C disease with an activator mitigates cholesterol accumulation
title_full Targeting defective sphingosine kinase 1 in Niemann–Pick type C disease with an activator mitigates cholesterol accumulation
title_fullStr Targeting defective sphingosine kinase 1 in Niemann–Pick type C disease with an activator mitigates cholesterol accumulation
title_full_unstemmed Targeting defective sphingosine kinase 1 in Niemann–Pick type C disease with an activator mitigates cholesterol accumulation
title_sort Targeting defective sphingosine kinase 1 in Niemann–Pick type C disease with an activator mitigates cholesterol accumulation
dc.creator.none.fl_str_mv Newton, Jason
Palladino, Elisa N.D.
Weigel, Cynthia
Maceyka, Michael
Gräler, Markus H.
Senkal, Can E.
Enriz, Ricardo Daniel
Marvanova, Pavlina
Jampilek, Josef
Lima, Santiago
Milstien, Sheldon
Spiegel, Sarah
author Newton, Jason
author_facet Newton, Jason
Palladino, Elisa N.D.
Weigel, Cynthia
Maceyka, Michael
Gräler, Markus H.
Senkal, Can E.
Enriz, Ricardo Daniel
Marvanova, Pavlina
Jampilek, Josef
Lima, Santiago
Milstien, Sheldon
Spiegel, Sarah
author_role author
author2 Palladino, Elisa N.D.
Weigel, Cynthia
Maceyka, Michael
Gräler, Markus H.
Senkal, Can E.
Enriz, Ricardo Daniel
Marvanova, Pavlina
Jampilek, Josef
Lima, Santiago
Milstien, Sheldon
Spiegel, Sarah
author2_role author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv CHOLESTEROL
GENETIC DISORDER
LIPID METABOLISM
LYSOSOMAL STORAGE DISEASE
NEURODEGENERATION
NIEMANN–PICK TYPE C
NPC1
SPHINGOLIPID
SPHINGOLIPIDS
SPHINGOSINE KINASE
SPHINGOSINE KINASE (SPHK)
SPHINGOSINE-1-PHOSPHATE (S1P)
topic CHOLESTEROL
GENETIC DISORDER
LIPID METABOLISM
LYSOSOMAL STORAGE DISEASE
NEURODEGENERATION
NIEMANN–PICK TYPE C
NPC1
SPHINGOLIPID
SPHINGOLIPIDS
SPHINGOSINE KINASE
SPHINGOSINE KINASE (SPHK)
SPHINGOSINE-1-PHOSPHATE (S1P)
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.4
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv 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.
Fil: Newton, Jason. Virginia Commonwealth University School of Medicine; Estados Unidos
Fil: Palladino, Elisa N.D.. Virginia Commonwealth University School of Medicine; Estados Unidos
Fil: Weigel, Cynthia. Virginia Commonwealth University School of Medicine; Estados Unidos
Fil: Maceyka, Michael. Virginia Commonwealth University School of Medicine; Estados Unidos
Fil: Gräler, Markus H.. Universitätsklinikum Jena; Alemania
Fil: Senkal, Can E.. Virginia Commonwealth University School of Medicine; Estados Unidos
Fil: Enriz, Ricardo Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina
Fil: Marvanova, Pavlina. Veterinární univerzita Brno; República Checa
Fil: Jampilek, Josef. Univerzita Komenského v Bratislave; Eslovaquia
Fil: Lima, Santiago. Virginia Commonwealth University; Estados Unidos
Fil: Milstien, Sheldon. Virginia Commonwealth University School of Medicine; Estados Unidos
Fil: Spiegel, Sarah. Virginia Commonwealth University School of Medicine; Estados Unidos
description 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.
publishDate 2020
dc.date.none.fl_str_mv 2020-07
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/136433
Newton, Jason; Palladino, Elisa N.D.; Weigel, Cynthia; Maceyka, Michael; Gräler, Markus H.; et al.; Targeting defective sphingosine kinase 1 in Niemann–Pick type C disease with an activator mitigates cholesterol accumulation; American Society for Biochemistry and Molecular Biology; Journal of Biological Chemistry (online); 295; 27; 7-2020; 9121-9134
0021-9258
1083-351X
CONICET Digital
CONICET
url http://hdl.handle.net/11336/136433
identifier_str_mv Newton, Jason; Palladino, Elisa N.D.; Weigel, Cynthia; Maceyka, Michael; Gräler, Markus H.; et al.; Targeting defective sphingosine kinase 1 in Niemann–Pick type C disease with an activator mitigates cholesterol accumulation; American Society for Biochemistry and Molecular Biology; Journal of Biological Chemistry (online); 295; 27; 7-2020; 9121-9134
0021-9258
1083-351X
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1074/jbc.RA120.012659
info:eu-repo/semantics/altIdentifier/url/https://www.jbc.org/article/S0021-9258(17)50333-6/fulltext
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv American Society for Biochemistry and Molecular Biology
publisher.none.fl_str_mv American Society for Biochemistry and Molecular Biology
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 12.993085

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