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Cytotoxicity of 1-deoxysphingolipid unraveled by genome-wide genetic screens and lipidomics in Saccharomyces cerevisiae

Hereditary sensory and autonomic neuropathy (HSAN) types IA and IC (IA/C) are caused by elevated levels of an atypical class of lipid named 1-deoxysphingolipid (DoxSL). How elevated levels of DoxSL perturb the physiology of the cell and how the perturbations lead to HSAN IA/C are largely unknown. In...

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Detalles Bibliográficos
Autores principales: Haribowo, A. Galih, Hannich, J. Thomas, Michel, Agnès H., Megyeri, Márton, Schuldiner, Maya, Kornmann, Benoît, Riezman, Howard
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The American Society for Cell Biology 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6789163/
https://www.ncbi.nlm.nih.gov/pubmed/31509475
http://dx.doi.org/10.1091/mbc.E19-07-0364
Descripción
Sumario:Hereditary sensory and autonomic neuropathy (HSAN) types IA and IC (IA/C) are caused by elevated levels of an atypical class of lipid named 1-deoxysphingolipid (DoxSL). How elevated levels of DoxSL perturb the physiology of the cell and how the perturbations lead to HSAN IA/C are largely unknown. In this study, we show that C(26)-1-deoxydihydroceramide (C(26)-DoxDHCer) is highly toxic to the cell, while C(16)- and C(18)-DoxDHCer are less toxic. Genome-wide genetic screens and lipidomics revealed the dynamics of DoxSL accumulation and DoxSL species responsible for the toxicity over the course of DoxSL accumulation. Moreover, we show that disruption of F-actin organization, alteration of mitochondrial shape, and accumulation of hydrophobic bodies by DoxSL are not sufficient to cause complete cellular failure. We found that cell death coincides with collapsed ER membrane, although we cannot rule out other possible causes of cell death. Thus, we have unraveled key principles of DoxSL cytotoxicity that may help to explain the clinical features of HSAN IA/C.