Coordination Funds

• Applicant: Professor Dr. Thomas Braulke
• Subject Area: Cell Biology
• Term: since 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 323732846

Lysosomes control the degradation, processing and recycling of macromolecules and damaged organelles delivered to lysosomes through the biosynthetic, endocytic, phagocytic, or autophagic routes. Lysosomal function is maintained by ~ 70 hydrolytic enzymes, accessory proteins and more than 250 membrane proteins, transporters and ion channels involved in pH and ion homeostasis or translocation of degradation products to the cytosol. More than 50 proteins have been identified on the cytosolic surface of lysosomes mediating membrane contacts and fusion with other organelles, lysosome reformation, motility and positioning, nutrient or energy sensing, and lysosome-to-nucleus signaling to maintain proper cell and organ physiology. These exciting discoveries have changed our view on the function of lysosomes from merely degradative compartments to dynamic structures implicated in adaptive responses to metabolic, developmental and environmental cues. Changes in lysosomal function do not only cause lysosomal storage disorders, but also play central roles in pathogenesis, e.g. of neurodegenerative and metabolic diseases or cancer. Moreover, the extracellular environment, intracellular signaling pathways and inflammatory conditions modulate the development and progression of lysosome-associated diseases. In many cases it remains unknown how the onset of disease is linked to lysosomal dysfunction. The Research Unit comprises internationally recognized senior and junior scientists from Germany and The Netherlands with a broad expertise in research on lysosomes, autophagy and lysosomal diseases. FOR will continue to capitalize on its synergistic collaborative approach to address key open questions in lysosome biology: Specifically, we aim to (1) mechanistically dissect how the protein machineries involved in biosynthetic and endocytic transport to and from lysosomes and in lysosomal signaling affect their function and biogenesis, including the analysis of protein ubiquitination, phosphorylation and acetylation. Moreover, (2) we will analyze lysosome-organelle contact sites and the machinery for autophagosome-lysosome fusion and lysosome reformation, and (3) the mechanisms that control lysosome motility and positioning. To accomplish these ambitious goals the consortium will combine sophisticated methodologies ranging from proteome, interactome, ubiquitome and lipidome analyses, characterization of new transgenic mouse models, to super resolution imaging and (immuno)electron microscopy. The consortium will continue to exchange reagents, methodological expertise, new findings and infrastructure to foster research and to further our understanding of lysosome biology. Advancing our knowledge of the molecular mechanisms underlying the various functions of lysosomes in the maintenance of cell and organismal homeostasis is a prerequisite to understand the pathomechanisms causing lysosome-related diseases and for the development of novel therapeutic strategies.

• DFG Programme: Research Units
• Subproject of: FOR 2625: Mechanisms of Lysosomal Homeostasis