Cellular Homeostasis and Cholesterol Regulation by the transporter Dispatched

• Applicant: Professor Dr. Kay Grobe
• Subject Area: Cell Biology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 568781320

The 12-pass transmembrane protein Dispatched (Disp1 in vertebrates and dDisp in insects) plays an essential role in Hedgehog (Hh) signaling by solubilizing C-terminally cholesterylated Hh from the plasma membrane (PM) of source cells. In addition to this established Disp function, we recently found that Disp1 also transfers free (non-esterified) PM cholesterol from human cells to soluble extracellular high-density lipoprotein (HDL) acceptors. As a consequence, Disp1-deficient human cells accumulate free cholesterol and strongly downregulate the expression of all relevant genes involved in cholesterol uptake or biosynthesis. This newly discovered non-canonical function of Disp1 as a major exporter of free PM cholesterol affects multiple aspects of cellular behavior: Our preliminary transcriptomic data indicate strongly altered expression of several gene clusters related to mitochondrial function and oxidative stress. We will use state of the art biochemistry, cell biology, and Drosophila genetics to establish that Disp affects cellular physiology independently of its known role in regulating Hh signaling, with highly relevant implications for human (patho)physiology.

• DFG Programme: Research Grants
• International Connection: France
• Cooperation Partner: Pascal Thérond, Ph.D.