Plasticity of STARD3-mediated sterol and sphingolipid transport at lysosome-ER contact sites (P16#)

• Subject Area: Cell Biology ; Biochemistry
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 467522186

The endolysosomal system constantly facilitates the recycling of cellular lipids. The transport of lipids to and from lysosomes is of particular interest as imbalances in this process have been linked to severe human pathologies. Lysosomal transport has so far been mostly elucidated for sterols, as lysosomes are integral to incorporating lipoprotein-derived cholesterol into cellular membranes. In contrast, transport of other lipids such as sphingolipids is much more enigmatic. In our previous work, we utilized multifunctional synthetic lipid analogs to resolve lipid transport and metabolism in an organelle-targeted manner. In this way, we found that sphingosine is exported from the lysosomal membrane by a transmembrane sterol transporter STARD3. STARD3 tethers lysosome-ER membrane contact sites (MCS) and fuels lysosomal sphingosine towards the synthesis of more complex sphingolipids in the ER and Golgi. This project will follow up and expand this finding by pursuing three objectives: 1) Obtaining a deeper understanding of the function of STARD3-mediated lysosome-ER MCS by unravelling their molecular architecture. 2) Zooming in on the molecular basis of sphingosine binding and transport by the lipid transfer domain of STARD3 using structural and biochemical methods and 3) Elucidating the plasticity of STARD3 function in health and models of lysosomal pathologies.

• DFG Programme: Collaborative Research Centres
• Subproject of: SFB 1557: Functional Plasticity encoded by Cellular Membrane Networks
• Applicant Institution: Universität Osnabrück
• Project Head: Dr. Denisa Jamecna