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Control of vacuole membrane homeostasis by a resident PI-3,5-kinase inhibitor

Stefan, CJ; (2018) Control of vacuole membrane homeostasis by a resident PI-3,5-kinase inhibitor. Proceedings of the National Academy of Sciences of the United States of America , 115 (18) pp. 4684-4689. 10.1073/pnas.1722517115. Green open access

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Abstract

Lysosomes have an important role in cellular protein and organelle quality control, metabolism, and signaling. On the surface of lysosomes, the PIKfyve/Fab1 complex generates phosphatidylinositol 3,5-bisphosphate, PI-3,5-P2, which is critical for lysosomal membrane homeostasis during acute osmotic stress and for lysosomal signaling. Here, we identify the inverted BAR protein Ivy1 as an inhibitor of the Fab1 complex with a direct influence on PI-3,5- P2 levels and vacuole homeostasis. Ivy1 requires Ypt7 binding for its function, binds PI-3,5-P2, and interacts with the Fab1 kinase. Colocalization of Ivy1 and Fab1 is lost during osmotic stress. In agreement with Ivy1’s role as a Fab1 regulator, its overexpression blocks Fab1 activity during osmotic shock and vacuole fragmentation. Conversely, loss of Ivy1, or lateral relocalization of Ivy1 on vacuoles away from Fab1, results in vacuole fragmentation and poor growth. Our data suggest that Ivy1 modulates Fab1- mediated PI-3,5-P2 synthesis during membrane stress and may allow adjustment of the vacuole membrane environment.

Type: Article
Title: Control of vacuole membrane homeostasis by a resident PI-3,5-kinase inhibitor
Open access status: An open access version is available from UCL Discovery
DOI: 10.1073/pnas.1722517115
Publisher version: http://dx.doi.org/10.1073/pnas.1722517115
Language: English
Additional information: Copyright © 2018 the Author(s). Published by PNAS. This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND).
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Lab for Molecular Cell Bio MRC-UCL
URI: https://discovery.ucl.ac.uk/id/eprint/10047310
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