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PIKfyve inhibition reveals a novel role for Inpp4b in the regulation of PtdIns(3)P and lysosome dynamics

Golam T. Saffi, Emily M. Mangialardi, View ORCID ProfileJean Vacher, View ORCID ProfileRoberto J. Botelho, View ORCID ProfileLeonardo Salmena
doi: https://doi.org/10.1101/2021.12.13.472440
Golam T. Saffi
1Department of Pharmacology & Toxicology, University of Toronto, Toronto, Ontario, Canada
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Emily M. Mangialardi
1Department of Pharmacology & Toxicology, University of Toronto, Toronto, Ontario, Canada
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Jean Vacher
2Institut de Recherches Cliniques de Montréal (IRCM), Département de Médecine, Université de Montréal, Montréal, Québec, Canada
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Roberto J. Botelho
3Department of Chemistry and Biology, Ryerson University, Toronto, Ontario, Canada
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Leonardo Salmena
1Department of Pharmacology & Toxicology, University of Toronto, Toronto, Ontario, Canada
4Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
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  • For correspondence: leonardo.salmena@utoronto.ca
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ABSTRACT

Lysosome membranes contain diverse phosphoinositide (PtdIns) lipids that co-ordinate lysosome function and dynamics. The PtdIns repertoire on lysosomes is tightly regulated by the action of diverse PtdIns kinases and phosphatases. Specific roles for PtdIns in lysosomal function and dynamics are currently unclear and require further investigation. PIKfyve, a lipid kinase which synthesizes PtdIns(3,5)P2 from PtdIns(3)P, controls lysosome “fusion-fission” cycles dynamics, autophagosome turnover and endocytic cargo delivery. We have recently characterized a role for INPP4B, a PtdIns phosphatase which hydrolyses PtdIns(3,4)P2 to form PtdIns(3)P, in the regulation of lysosomal biogenesis and function. To gain a better understanding of PtdIns homeostasis on lysosomes, we investigated the consequence of disrupting PIKfyve in Inpp4b-deficient mouse embryonic fibroblasts. Surprisingly, simultaneous inhibition of Inpp4b and PIKfyve functions impair lysosome “fission” dynamics and thereby exacerbate lysosome enlargement, inhibit autophagic flux. Further examination into the underlying processes that may explain exaggerated lysosome enlargement revealed elevated levels of lysosome associated PtdIns(3)P as contributing factors that control lysosome morphology in cells where Inpp4b and PIKfyve are disrupted. Overall, our study suggests that lysosomal functions are regulated by Inpp4b, through a paradoxical role in suppressing the induction of PtdIns(3)P production.

SUMMARY STATEMENT In this study we identify a novel crosstalk between Inpp4b and PIKfyve. This crosstalk regulates lysosome membrane phosphoinositide composition and lysosomal homeostasis. Our data demonstrate that Inpp4b restricts VPS34-dependent induction of PtdIns(3)P levels, which is activated upon apilimod-mediated PIKfyve inhibition. Through this mechanism, Inpp4b contributes to the regulation of lysosomal membrane dynamics and homeostasis.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted December 14, 2021.
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PIKfyve inhibition reveals a novel role for Inpp4b in the regulation of PtdIns(3)P and lysosome dynamics
Golam T. Saffi, Emily M. Mangialardi, Jean Vacher, Roberto J. Botelho, Leonardo Salmena
bioRxiv 2021.12.13.472440; doi: https://doi.org/10.1101/2021.12.13.472440
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PIKfyve inhibition reveals a novel role for Inpp4b in the regulation of PtdIns(3)P and lysosome dynamics
Golam T. Saffi, Emily M. Mangialardi, Jean Vacher, Roberto J. Botelho, Leonardo Salmena
bioRxiv 2021.12.13.472440; doi: https://doi.org/10.1101/2021.12.13.472440

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