Babraham Distinguished Seminar - Lipid switches in cell physiology: From nutrient signals to disease

Babraham Distinguished Seminar - Lipid switches in cell physiology: From nutrient signals to disease

The Babraham Distinguished Seminar Series is sponsored by the Babraham Institute and the Babraham Research Campus which is home to more than 50 biotech companies. The seminars are also advertised to the wider Cambridge community. The series will provide exciting science talks by distinguished scientists from across the world in many areas of biomedical interest.

Professor Volker Haucke; Leibniz Forschungsinstitut für Molekulare Pharmakologie (FMP)

Following his PhD in biochemistry from the Biozentrum of the University of Basel and postdoctoral work at Yale University School of Medicine Volker Haucke established his own laboratory at the University of Göttingen. He was appointed as a full professor of biochemistry at the Freie Universiät Berlin in 2003. Since 2012 he is director at the Leibniz Forschungsinstitut für Molekulare Pharmakologie (FMP), professor of molecular pharmacology at Freie Universität Berlin and a member of the NeuroCure Cluster of Excellence. The focus of research in his laboratory is the dissection of the molecular mechanisms of endocytosis and endolysosomal membrane dynamics with a focus on the role of signaling lipids. The laboratory uses a wide range of technologies that include biochemical and cell biological approaches, electrophysiology, chemical biology, super-resolution and electron microscopy as well as genetic manipulations at the organismic level in vivo. His discoveries have provided insight into the roles of lipids in cell physiology and open new avenues for the treatment of human diseases ranging from cancer and thrombosis to neurological disorders.

Phosphoinositides (PIs) form a minor class of phospholipids with crucial functions in cell physiology, ranging from cell signalling and motility to a role as signposts of compartmental membrane identity and dynamics. In fed cells, phosphatidylinositol 3-phosphates are present at the plasma membrane and within the endosomal system, where they serve as key regulators of both cell signaling and of intracellular membrane dynamics, while PI 4-phosphates delineate the secretory pathway. In my talk I will discuss the localization, regulation, and molecular mechanism of action of PI kinases and phosphatases and their roles in endocytosis and within the endolysosomal system. Moreover, I will cover our recent advances in the analysis of the metabolic pathways that regulate the cellular synthesis and turnover of distinct PI phosphates at endosomes or lysosomes in response to altering nutrient conditions, discuss the mechanisms by which these lipids regulate endolysosomal membrane dynamics and metabolism, and provide examples of how dysregulation of these pathways may cause human disease. Our data provide a framework for how PI phosphate metabolism is integrated into the cellular network and identify PI kinases as targets for future therapeutics. References (1) Ebner, M. et al, Haucke, V. (2023) Nutrient regulated control of lysosome function by signaling lipid conversion. Cell 186, 5328-5346. doi: 10.1016/j.cell.2023.09.027 (2) Lo, W.T. et al, Haucke, V. (2023) Development of selective inhibitors of phosphatidylinositol 3-kinase C2α. Nat Chem Biol 19, 18-27. doi: 10.1038/s41589-022- 01118 (3) Jang, W. et al, Haucke, V. (2022) Endosomal lipid signalling reshapes the endoplasmic reticulum to control mitochondrial function. Science 378, eabq5209. DOI: 10.1126/science.abq5209 (4) Posor, Y.*, Jang, W.*, Haucke, V. (2022) Phosphoinositides as membrane organizers. Nat Rev Mol Cell Biol 23, 797-816. doi: 10.1038/s41580-022-00490-x (5) Lo, W.T. et al, Haucke, V. (2022) Structural basis of PI3KC2a function. Nat Struct Mol Biol. 29, 218- 228; doi: 10.1038/s41594-022-00730-w (6) Marat, A.L. et al, Haucke, V. (2017) mTORC1 activity repression by late endosomal phosphatidylinositol 3,4-bisphosphate. Science 356, 968-972.

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