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Monitoring the Effect of Osmotic Stress on Secretory Vesicles and Exocytosis
Published on: February 19, 2018
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A PP6-ASK3 Module Coordinates the Bidirectional Cell Volume Regulation under Osmotic Stress
Kengo Watanabe1, Tsuyoshi Umeda1, Kuniyoshi Niwa1
1Laboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan.
Cell Reports
|March 15, 2018
Summary
Cell volume regulation relies on regulatory volume decrease (RVD) and increase (RVI). This study reveals ASK3 controls both RVD and RVI, with PP6 inactivating ASK3 to manage RVI and cell survival during osmotic stress.
Area of Science:
- Cellular Biology
- Physiology
- Molecular Mechanisms
Background:
- Cell volume regulation is crucial for cellular function, involving regulatory volume decrease (RVD) and regulatory volume increase (RVI) in response to osmotic stress.
- The molecular pathways linking osmosensing to RVD/RVI induction are not well understood, and reciprocal responders in osmotic stress signaling are sparsely identified.
- Previous work identified ASK3 as a protein with bidirectional kinase activity changes under osmotic stress.
Purpose of the Study:
- To elucidate the role of ASK3 in both RVD and RVI.
- To identify molecular players involved in the osmosensing-to-RVD/RVI signaling pathway.
- To understand the mechanism of ASK3 regulation during osmotic stress.
Main Methods:
- High-content, genome-wide small interfering RNA (siRNA) screening to identify ASK3 regulators.
- Osmotic stress assays to observe cell volume changes (RVD/RVI).
- Co-immunoprecipitation assays to study protein-protein interactions and kinase activity assays.
Main Results:
- ASK3 was confirmed to control both RVD and RVI.
- A genome-wide siRNA screen identified protein phosphatase 6 (PP6) as a direct ASK3 inactivator.
- PP6 interacts with ASK3 in an osmolality-dependent manner, inactivating ASK3 to promote RVI and cell survival under hyperosmotic stress.
Conclusions:
- The PP6-ASK3 interaction is a key component of the bidirectional osmotic stress response.
- ASK3 acts as a central regulator for both RVD and RVI.
- This interaction provides a molecular link between osmosensing and the cellular volume recovery systems, ensuring cell survival.
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