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HEIndividual fellowship2022–2025

PIP-AID · Characterization of the role of Sac1 in the spatiotemporally controlled interplay between PI4P and cholesterol homeostasis

Horizon Europe — Marie Skłodowska-Curie Actions

Duration
2022-11-01 → 2025-07-31
EU contribution
€218,652
Participants
1
Scheme
HORIZON-TMA-MSCA-PF-EF

Lines connect the coordinator with its partners.

Results in brief

Characterization of the role of Sac1 in the spatiotemporally controlled interplay between PI4P and cholesterol homeostasis

Phosphatidylinositol 4 phosphate (PI4P) is the most abundant phosphoinositide lipid species in the cell. It is asymmetrically distributed over the cell and has essential functions in secretory trafficking, membrane identity and lipid metabolism. Disruptions in cellular PI4P levels can give rise to neuro-degenerative diseases including ALS and Alzheimer’s disease. PI4P levels are regulated by an interplay between PI4-kinases and the integral ER/Golgi phosphatase Sac1. Sac1 tightly controls distinct PI4P membrane pools, maintaining the asymmetrical distribution of PI4P through the cell. This is important to fuel non-vesicular lipid transfer at membrane contact sites, mediated by lipid transfer proteins. e.g. OSBP, which mediates the transport of cholesterol from the ER to the Golgi, in exchange for PI4P. Sac1 is the only known PI4P phosphatase and is essential for cell viability. Sac1 knockout in mice or fruit fly results in early embryonic lethality. In this study we used auxin-inducible degradation of Sac1, to assess the acute effects of Sac1 loss. Overall, we aimed to contribute to a deeper and systematic understanding into the regulatory role of Sac1 in lipid metabolism and Golgi functioning and provide a new means to investigate the unexplored role of Sac1 in development.

Data: CORDIS, © European Union

Project objective

Lipids are essential components of cell membranes. Every organelle membrane is constituted of a unique composition of different lipid species. This distinctive lipid distribution along organelle membranes is important to maintain the identity and functions of the different organelles. In this research project, I aim to understand how the lipid species phosphatidylinositol-4-phosphate (PI4P) is regulated and how this affects lipid homeostasis and cellular functioning. The PI4P distribution is important for intracellular signalling, lipid and protein trafficking. Alterations in PI4P levels may contribute to the progression of other neurodegenerative disorders, e.g. Alzheimer's disease. In this project, I will study the PI4P phosphatase Sac1. Sac1 consumes PI4P in the endoplasmic reticulum or Golgi apparatus. This locally lowers PI4P levels, therefore maintaining the asymmetric distribution of PI4P in the cell. The PI4P gradient is important for the transport of lipids and proteins. In cell models, Sac1 knockdown or knockout severely compromises cell viability, whereas Sac1 knockout mouse or drosophila are embryonically lethal. This highlights the importance of Sac1, however, making it difficult to examine the physiological functions of Sac1. In this project, I will use an auxin-inducible degradation (AID) system to induce the degradation of Sac1 within one hour. This allows me to assess the acute effects of Sac1 depletion. Using this model, I will address the following key objectives: 1) Examine the role of Sac1 in lipid homeostasis. 2) Investigate the regulatory mechanism of Sac1 in Golgi morphology and kinetics, and 3) Characterize a inducible degradation system in zebrafish. By employing the AID system in a zebrafish model, I aim to provide a new means to study the role of Sac1 in development. Taken together, this project will contribute to deeper insights into the regulatory function of Sac1 in lipid homeostasis and selective protein secretion.

Original text from CORDIS.

Participants

  • HELSINGIN YLIOPISTO · HelsinkiCoordinatorFinland

Links

Data: CORDIS, © European Union