Sphingosine Kinase Regulates Microtubule Dynamics and Organelle Positioning Necessary for Proper G<sub>1</sub>/S Cell Cycle Transition in <named-content content-type="genus-species">Trypanosoma brucei</named-content>

ABSTRACT Sphingolipids are important constituents of cell membranes and also serve as mediators of cell signaling and cell recognition. Sphingolipid metabolites such as sphingosine-1-phosphate and ceramide regulate signaling cascades involved in cell proliferation and differentiation, autophagy, inf...

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Autores principales:	Deborah A. Pasternack, Aabha I. Sharma, Cheryl L. Olson, Conrad L. Epting, David M. Engman
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2015
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/a49dc15d4be941208c9c85c064f14495
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spelling	oai:doaj.org-article:a49dc15d4be941208c9c85c064f144952021-11-15T15:41:30ZSphingosine Kinase Regulates Microtubule Dynamics and Organelle Positioning Necessary for Proper G<sub>1</sub>/S Cell Cycle Transition in <named-content content-type="genus-species">Trypanosoma brucei</named-content>10.1128/mBio.01291-152150-7511https://doaj.org/article/a49dc15d4be941208c9c85c064f144952015-10-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01291-15https://doaj.org/toc/2150-7511ABSTRACT Sphingolipids are important constituents of cell membranes and also serve as mediators of cell signaling and cell recognition. Sphingolipid metabolites such as sphingosine-1-phosphate and ceramide regulate signaling cascades involved in cell proliferation and differentiation, autophagy, inflammation, and apoptosis. Little is known about how sphingolipids and their metabolites function in single-celled eukaryotes. In the present study, we investigated the role of sphingosine kinase (SPHK) in the biology of the protozoan parasite Trypanosoma brucei, the agent of African sleeping sickness. T. brucei SPHK (TbSPHK) is constitutively but differentially expressed during the life cycle of T. brucei. Depletion of TbSPHK in procyclic-form T. brucei causes impaired growth and attenuation in the G1/S phase of the cell cycle. TbSPHK-depleted cells also develop organelle positioning defects and an accumulation of tyrosinated α-tubulin at the elongated posterior end of the cell, known as the “nozzle” phenotype, caused by other molecular perturbations in this organism. Our studies indicate that TbSPHK is involved in G1-to-S cell cycle progression, organelle positioning, and maintenance of cell morphology. Cytotoxicity assays using TbSPHK inhibitors revealed a favorable therapeutic index between T. brucei and human cells, suggesting TbSPHK to be a novel drug target. IMPORTANCE Trypanosoma brucei is a single-celled parasite that is transmitted between humans and other animals by the tsetse fly. T. brucei is endemic in sub-Saharan Africa, where over 70 million people and countless livestock are at risk of developing T. brucei infection, called African sleeping sickness, resulting in economic losses of ~$35 million from the loss of cattle alone. New drugs for this infection are sorely needed and scientists are trying to identify essential enzymes in the parasite that can be targets for new therapies. One possible enzyme target is sphingosine kinase, an enzyme involved in the synthesis of lipids important for cell surface integrity and regulation of cell functions. In this study, we found that sphingosine kinase is essential for normal growth and structure of the parasite, raising the possibility that it could be a good target for new chemotherapy for sleeping sickness.Deborah A. PasternackAabha I. SharmaCheryl L. OlsonConrad L. EptingDavid M. EngmanAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 6, Iss 5 (2015)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Deborah A. Pasternack Aabha I. Sharma Cheryl L. Olson Conrad L. Epting David M. Engman Sphingosine Kinase Regulates Microtubule Dynamics and Organelle Positioning Necessary for Proper G<sub>1</sub>/S Cell Cycle Transition in <named-content content-type="genus-species">Trypanosoma brucei</named-content>
description	ABSTRACT Sphingolipids are important constituents of cell membranes and also serve as mediators of cell signaling and cell recognition. Sphingolipid metabolites such as sphingosine-1-phosphate and ceramide regulate signaling cascades involved in cell proliferation and differentiation, autophagy, inflammation, and apoptosis. Little is known about how sphingolipids and their metabolites function in single-celled eukaryotes. In the present study, we investigated the role of sphingosine kinase (SPHK) in the biology of the protozoan parasite Trypanosoma brucei, the agent of African sleeping sickness. T. brucei SPHK (TbSPHK) is constitutively but differentially expressed during the life cycle of T. brucei. Depletion of TbSPHK in procyclic-form T. brucei causes impaired growth and attenuation in the G1/S phase of the cell cycle. TbSPHK-depleted cells also develop organelle positioning defects and an accumulation of tyrosinated α-tubulin at the elongated posterior end of the cell, known as the “nozzle” phenotype, caused by other molecular perturbations in this organism. Our studies indicate that TbSPHK is involved in G1-to-S cell cycle progression, organelle positioning, and maintenance of cell morphology. Cytotoxicity assays using TbSPHK inhibitors revealed a favorable therapeutic index between T. brucei and human cells, suggesting TbSPHK to be a novel drug target. IMPORTANCE Trypanosoma brucei is a single-celled parasite that is transmitted between humans and other animals by the tsetse fly. T. brucei is endemic in sub-Saharan Africa, where over 70 million people and countless livestock are at risk of developing T. brucei infection, called African sleeping sickness, resulting in economic losses of ~$35 million from the loss of cattle alone. New drugs for this infection are sorely needed and scientists are trying to identify essential enzymes in the parasite that can be targets for new therapies. One possible enzyme target is sphingosine kinase, an enzyme involved in the synthesis of lipids important for cell surface integrity and regulation of cell functions. In this study, we found that sphingosine kinase is essential for normal growth and structure of the parasite, raising the possibility that it could be a good target for new chemotherapy for sleeping sickness.
format	article
author	Deborah A. Pasternack Aabha I. Sharma Cheryl L. Olson Conrad L. Epting David M. Engman
author_facet	Deborah A. Pasternack Aabha I. Sharma Cheryl L. Olson Conrad L. Epting David M. Engman
author_sort	Deborah A. Pasternack
title	Sphingosine Kinase Regulates Microtubule Dynamics and Organelle Positioning Necessary for Proper G<sub>1</sub>/S Cell Cycle Transition in <named-content content-type="genus-species">Trypanosoma brucei</named-content>
title_short	Sphingosine Kinase Regulates Microtubule Dynamics and Organelle Positioning Necessary for Proper G<sub>1</sub>/S Cell Cycle Transition in <named-content content-type="genus-species">Trypanosoma brucei</named-content>
title_full	Sphingosine Kinase Regulates Microtubule Dynamics and Organelle Positioning Necessary for Proper G<sub>1</sub>/S Cell Cycle Transition in <named-content content-type="genus-species">Trypanosoma brucei</named-content>
title_fullStr	Sphingosine Kinase Regulates Microtubule Dynamics and Organelle Positioning Necessary for Proper G<sub>1</sub>/S Cell Cycle Transition in <named-content content-type="genus-species">Trypanosoma brucei</named-content>
title_full_unstemmed	Sphingosine Kinase Regulates Microtubule Dynamics and Organelle Positioning Necessary for Proper G<sub>1</sub>/S Cell Cycle Transition in <named-content content-type="genus-species">Trypanosoma brucei</named-content>
title_sort	sphingosine kinase regulates microtubule dynamics and organelle positioning necessary for proper g<sub>1</sub>/s cell cycle transition in <named-content content-type="genus-species">trypanosoma brucei</named-content>
publisher	American Society for Microbiology
publishDate	2015
url	https://doaj.org/article/a49dc15d4be941208c9c85c064f14495
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Sphingosine Kinase Regulates Microtubule Dynamics and Organelle Positioning Necessary for Proper G<sub>1</sub>/S Cell Cycle Transition in <named-content content-type="genus-species">Trypanosoma brucei</named-content>

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