FOR 2625:  Mechanisms of Lysosomal Homeostasis

• Subject Area: Biology ; Medicine
• Term: since 2017
• Website: Homepage
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 323732846

Lysosomes can degrade materials delivered by endocytosis, phagocytosis and autophagy, which is achieved by the concerted action of 60 luminal acid hydrolases and more than 200 integral membrane proteins involved in luminal acidification and ion composition, translocation of degradation products to the cytosol and in contact and fusion with other organelles. Although lysosomal protein defects have been known to be the cause for a plethora of different rare diseases for a long time, in recent years, the view on the function of lysosomes as a purely degradative compartment has changed towards lysosomes as a central player in adaptive responses to metabolic, developmental and environmental cues by lysosome-nucleus signaling processes. In consideration of this development, prominent senior and junior scientists from Germany and The Netherlands with diverse expertise and high international reputation in the field of lysosomes, autophagy, and lysosomal storage disorders apply here for the establishment of a novel interdisciplinary network, the Lysosome Research Unit. The consortium will analyse in synergistic collaborations the biogenesis, functions and turnover of lysosomes as a whole, and protein-protein and lipid-protein interactions at the cytosolic surface of lysosomes, as well as adaptive regulatory mechanisms to compensate lysosomal dysfunctions. The research program addresses three key aims: First, we aim to identify how phosphatidylinositides at the lysosomal surface and their interacting proteins modulate autophagy, autophagosome-lysosome reformation, lysosomal signaling, lysosome positioning, and exocytosis. Second, we aim to identify novel components of the molecular sorting machinery and the impact of ubiquitination and ion transport across membranes, on the LAMP and mannose 6-phosphate receptor (MPR) pathway as well as on the turnover of lysosomal proteins essential for lysosomal homeostasis. Third, we will examine the role of posttranslational modifications of transcription factors EB and E3 on the lysosomal proteome, and lysosome-nucleus signaling processes initiated by dysfunctional lysosomes and other signaling pathways in the cell.The basic understanding of molecular mechanisms maintaining lysosomal homeostasis is a prerequisite to examine pathomechanisms of related lysosomal disorders, and for the development of long-term preclinical therapeutic strategies.

• DFG Programme: Research Units
• International Connection: Netherlands

Projects

• A role for human WIPI3 in lysosomal phosphoinositide signaling (Applicant Proikas-Cezanne, Tassula )
• Cell type-specific roles of lysosomal chloride/proton exchange (Applicants Jentsch, Thomas J. ;  Stauber, Tobias )
• Coordination Funds (Applicant Braulke, Thomas )
• Lysosomal gene transcription and protein expression (Applicants Braulke, Thomas ;  Winter, Dominic )
• Mechanism of regulation of lysosome biogenesis and function by cellular ion homeostasis (Applicant Haucke, Ph.D., Volker )
• Quantitative determination of the effect of transcription factors TFEB and TFE3 on the expression of lysosomal proteins (Applicants Gieselmann, Volkmar ;  Winter, Dominic )
• Regulation of TMEM55A/B-dependent positioning of lysosomes (Applicant Damme, Markus )
• The role of AP-5 in the endolysosomal system, autophagy and autophagic lysosome reformation (Applicant Hübner, Christian Andreas )
• Ubiquitination in regulation of lysosome functions (Applicants Bremm, Anja ;  Dikic, Ivan )
• Understanding the role of the Lysosomal Integral Membrane Protein type 2 (LIMP-2/SCARB2) in lysosomal lipid transport (Applicant Saftig, Paul )
• Unravelling HOPS dependent and independent mechanisms of VPS41 function in neuronal lysosome biogenesis (Applicant Klumperman, Ph.D., Judith )

• Spokesperson: Professor Dr. Thomas Braulke