Loss of functional MYO1C-myosin 1c, a motor protein involved in lipid raft trafficking, disrupts autophagosome-­lysosome fusionReportar como inadecuado


Loss of functional MYO1C-myosin 1c, a motor protein involved in lipid raft trafficking, disrupts autophagosome-­lysosome fusion


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Publication Date: 2015-01-28

Journal Title: Autophagy

Publisher: Taylor & Francis

Volume: 10

Issue: 12

Pages: 2310-2323

Language: English

Type: Article

Metadata: Show full item record

Citation: Brandstaetter, H., Kishi-­Itakura, C., Tumbarello, D. A., Manstein, D. J., & Buss, F. (2015). Loss of functional MYO1C/myosin 1c, a motor protein involved in lipid raft trafficking, disrupts autophagosome-­lysosome fusion. Autophagy, 10 (12), 2310-2323.

Description: This is the final published version. It first appeared at http://www.tandfonline.com/doi/abs/10.4161/15548627.2014.984272#.VNo0Gy6Qne4.

Abstract: MYO1C, a single-headed class I myosin, associates with cholesterol-enriched lipid rafts and facilitates their recycling from intracellular compartments to the cell surface. Absence of functional MYO1C disturbs the cellular distribution of lipid rafts, causes the accumulation of cholesterol-enriched membranes in the perinuclear recycling compartment, and leads to enlargement of endolysosomal membranes. Several feeder pathways, including classical endocytosis but also the autophagy pathway, maintain the health of the cell by selective degradation of cargo through fusion with the lysosome. Here we show that loss of functional MYO1C leads to an increase in total cellular cholesterol and its disrupted subcellular distribution. We observe an accumulation of autophagic structures caused by a block in fusion with the lysosome and a defect in autophagic cargo degradation. Interestingly, the loss of MYO1C has no effect on degradation of endocytic cargo such as EGFR, illustrating that although the endolysosomal compartment is enlarged in size, it is functional, contains active hydrolases, and the correct pH. Our results highlight the importance of correct lipid composition in autophagosomes and lysosomes to enable them to fuse. Ablating MYO1C function causes abnormal cholesterol distribution, which has a major selective impact on the autophagy pathway.

Keywords: autophagy, cholesterol, electron microscopy, lipid raft, lysosome, MYO1C

Sponsorship: This work was financially supported by the Wellcome Trust (F.B., D.A.T. and H.B.), the Deutsche Forschungsgemeinschaft Grant MA 1081/19–1 (D.J.M) and the Medical Research Council (F.B and C. K.-I.). The CIMR is in receipt of a strategic award from the Wellcome Trust (100140).

Identifiers:

This record's URL: http://doi.org/10.4161/15548627.2014.984272http://www.repository.cam.ac.uk/handle/1810/246723

Rights: Attribution 2.0 UK: England & Wales

Licence URL: http://creativecommons.org/licenses/by/2.0/uk/





Autor: Brandstaetter, HemmaKishi-­Itakura, ChiekoTumbarello, David A.Manstein, Dietmar J.Buss, Folma

Fuente: https://www.repository.cam.ac.uk/handle/1810/246723



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