Lysosomes serve as final degradative compartments in eukaryotic cells and degrade intra- and extracellular material delivered by endocytosis, phagocytosis and autophagy. Degradation 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, only in recent years the view on 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.
The DFG-funded Research Unit FOR2625 “Mechanisms of Lysosomal Homeostasis” is an inter-disciplinary network consisting of 9 research groups located in Germany and one research group located in the Netherlands. The consortium aims at elucidating the molecular mechanisms of maintaining lysosomal homeostasis and the adaptive regulatory mechanisms to compensate lysosomal dysfunctions. The FOR2625 research program strongly benefits from the wide spread expertises of its members by synergistic collaborations and focusses on three key objectives:
Impact of phosphatidylinositides at the lysosomal surface and their interacting proteins on modulation of autophagy, autophagosome-lysosome reformation, lysosomal signaling, lysosome positioning, and exocytosis
Identifying novel components of the molecular sorting machinery and elucidating 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
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
The research of the FOR2625 will give valuable insight to the understanding of the molecular mechanisms underlying lysosomal biogenesis, function and turnover which is a prerequisite to examine pathomechanisms of related lysosomal disorders and to develop long-term preclinical therapeutic strategies.
The first funding period with a duration of 3 years started on October 1st 2017.