Cargando…

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

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-P(2), which is critical for lysosomal membrane homeostasis during acute osmotic...

Descripción completa

Detalles Bibliográficos
Autores principales: Malia, PC, Numrich, Johannes, Nishimura, Taki, González Montoro, Ayelén, Stefan, Christopher J., Ungermann, Christian
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5939101/
https://www.ncbi.nlm.nih.gov/pubmed/29674454
http://dx.doi.org/10.1073/pnas.1722517115
_version_ 1783320904316485632
author Malia, PC
Numrich, Johannes
Nishimura, Taki
González Montoro, Ayelén
Stefan, Christopher J.
Ungermann, Christian
author_facet Malia, PC
Numrich, Johannes
Nishimura, Taki
González Montoro, Ayelén
Stefan, Christopher J.
Ungermann, Christian
author_sort Malia, PC
collection PubMed
description 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-P(2), 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-P(2) levels and vacuole homeostasis. Ivy1 requires Ypt7 binding for its function, binds PI-3,5-P(2), 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-P(2) synthesis during membrane stress and may allow adjustment of the vacuole membrane environment.
format Online
Article
Text
id pubmed-5939101
institution National Center for Biotechnology Information
language English
publishDate 2018
publisher National Academy of Sciences
record_format MEDLINE/PubMed
spelling pubmed-59391012018-05-09 Control of vacuole membrane homeostasis by a resident PI-3,5-kinase inhibitor Malia, PC Numrich, Johannes Nishimura, Taki González Montoro, Ayelén Stefan, Christopher J. Ungermann, Christian Proc Natl Acad Sci U S A Biological Sciences 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-P(2), 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-P(2) levels and vacuole homeostasis. Ivy1 requires Ypt7 binding for its function, binds PI-3,5-P(2), 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-P(2) synthesis during membrane stress and may allow adjustment of the vacuole membrane environment. National Academy of Sciences 2018-05-01 2018-04-19 /pmc/articles/PMC5939101/ /pubmed/29674454 http://dx.doi.org/10.1073/pnas.1722517115 Text en Copyright © 2018 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/ This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) .
spellingShingle Biological Sciences
Malia, PC
Numrich, Johannes
Nishimura, Taki
González Montoro, Ayelén
Stefan, Christopher J.
Ungermann, Christian
Control of vacuole membrane homeostasis by a resident PI-3,5-kinase inhibitor
title Control of vacuole membrane homeostasis by a resident PI-3,5-kinase inhibitor
title_full Control of vacuole membrane homeostasis by a resident PI-3,5-kinase inhibitor
title_fullStr Control of vacuole membrane homeostasis by a resident PI-3,5-kinase inhibitor
title_full_unstemmed Control of vacuole membrane homeostasis by a resident PI-3,5-kinase inhibitor
title_short Control of vacuole membrane homeostasis by a resident PI-3,5-kinase inhibitor
title_sort control of vacuole membrane homeostasis by a resident pi-3,5-kinase inhibitor
topic Biological Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5939101/
https://www.ncbi.nlm.nih.gov/pubmed/29674454
http://dx.doi.org/10.1073/pnas.1722517115
work_keys_str_mv AT maliapc controlofvacuolemembranehomeostasisbyaresidentpi35kinaseinhibitor
AT numrichjohannes controlofvacuolemembranehomeostasisbyaresidentpi35kinaseinhibitor
AT nishimurataki controlofvacuolemembranehomeostasisbyaresidentpi35kinaseinhibitor
AT gonzalezmontoroayelen controlofvacuolemembranehomeostasisbyaresidentpi35kinaseinhibitor
AT stefanchristopherj controlofvacuolemembranehomeostasisbyaresidentpi35kinaseinhibitor
AT ungermannchristian controlofvacuolemembranehomeostasisbyaresidentpi35kinaseinhibitor