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

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.

Coordinator

HELSINGIN YLIOPISTO
Net EU contribution
€ 199 694,40
Address
Yliopistonkatu 3
00014 Helsingin Yliopisto
Finland

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Region
Manner-Suomi Helsinki-Uusimaa Helsinki-Uusimaa
Activity type
Higher or Secondary Education Establishments
Non-EU contribution
No data