Hypoxia controls plasma membrane targeting of polarity proteins by dynamic turnover of PI4P and PI(4,5)P2

  1. Juan Lu
  2. Wei Dong
  3. Gerald R Hammond  Is a corresponding author
  4. Yang Hong  Is a corresponding author
  1. University of Pittsburgh, China [CN]
  2. University of Pittsburgh, United States

Abstract

Phosphatidylinositol 4-phosphate (PI4P) and phosphatidylinositol 4,5-biphosphate (PIP2) are key phosphoinositides that determine the identity of the plasma membrane (PM) and regulate numerous key biological events there. To date, mechanisms regulating the homeostasis and dynamic turnover of PM PI4P and PIP2 in response to various physiological conditions and stresses remain to be fully elucidated. Here we report that hypoxia in Drosophila induces acute and reversible depletion of PM PI4P and PIP2 that severely disrupts the electrostatic PM targeting of multiple polybasic polarity proteins. Genetically encoded ATP sensors confirmed that hypoxia induces acute and reversible reduction of cellular ATP levels which showed a strong real-time correlation with the levels of PM PI4P and PIP2 in cultured cells. By combining genetic manipulations with quantitative imaging assays we showed that PI4KIIIα, as well as Rbo/EFR3 and TTC7 that are essential for targeting PI4KIIIα to PM, are required for maintaining the homeostasis and dynamic turnover of PM PI4P and PIP2 under normoxia and hypoxia. Our results revealed that in cells challenged by energetic stresses triggered by hypoxia, ATP inhibition and possibly ischemia, dramatic turnover of PM PI4P and PIP2 could have profound impact on many cellular processes including electrostatic PM targeting of numerous polybasic proteins.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files

Article and author information

Author details

  1. Juan Lu

    Department of Cell Biology, University of Pittsburgh, Pittsburgh, China [CN]
    Competing interests
    The authors declare that no competing interests exist.
  2. Wei Dong

    Department of Cell Biology, University of Pittsburgh, Pittsburgh, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Gerald R Hammond

    Department of Cell Biology, University of Pittsburgh, Pittsburgh, United States
    For correspondence
    ghammond@pitt.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6660-3272
  4. Yang Hong

    Department of Cell Biology, University of Pittsburgh, Pittsburgh, United States
    For correspondence
    yhong@pitt.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2252-0798

Funding

National Institute of General Medical Sciences (R01GM121534)

  • Yang Hong

National Institute of General Medical Sciences (R01GM086423)

  • Yang Hong

National Institute of General Medical Sciences (R35GM119412)

  • Gerald R Hammond

National Institute of General Medical Sciences (R21RR024869)

  • Yang Hong

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Elisabeth Knust, Max-Planck Institute of Molecular Cell Biology and Genetics, Germany

Publication history

  1. Received: April 20, 2022
  2. Accepted: June 6, 2022
  3. Accepted Manuscript published: June 9, 2022 (version 1)

Copyright

© 2022, Lu et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Juan Lu
  2. Wei Dong
  3. Gerald R Hammond
  4. Yang Hong
(2022)
Hypoxia controls plasma membrane targeting of polarity proteins by dynamic turnover of PI4P and PI(4,5)P2
eLife 11:e79582.
https://doi.org/10.7554/eLife.79582

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