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UK funding (£639,516): Organelle remodelling and function of endolysosomes, lysosomes and secretory lysosomes Ukri1 Jan 2025 UK Research and Innovation, United Kingdom
Overview
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Organelle remodelling and function of endolysosomes, lysosomes and secretory lysosomes
| Abstract | The interior of mammalian cells is compartmentalized into specialized organelles with cargo being moved between these compartments by the trafficking of vesicles or tubules (little bubbles surrounded by a thin membrane made of a fatty substance called phospholipid and studded with proteins). Cargo, including trans-membrane and soluble proteins, is taken up into cells by a process called endocytosis in which vesicles formed at the cell surface deliver their cargo to the endocytic system. This consists of organelles called endosomes, endolysosomes and lysosomes. These organelles play a major role in cellular signalling, nutrition and homeostasis. Their aberrant function is linked to many pathophysiological states and they are a major site of bacterial, viral and protozoal pathogen entry into cells. Endosomes, endolysosomes and lysosomes are very dynamic organelles. They undergo constant cycles of remodelling as a result of fusion events between endosomes and lysosomes to form endolysosomes and the coupled reformation of lysosomes from endolysosomes. A key part of the re-modelling involves controlling the acidity of the lumen of these organelles. This ensures that endolysosomes, the principal site of cargo degradation, are very acidic, but terminal storage lysosomes are not acidic and therefore non-degradative. The acidity is controlled by the two-part tvacuolar ATPase (V-ATPase), a protein complex located in the membrane surrounding these organelles. The V-ATPase is a nanomachine powered by the hydrolysis of ATP and pumps hydrogen ions into the organelles to increase lumenal acidity. Its activity is mainly regulated by the state of assembly/disassembly of its two parts, The main aims and objectives of our proposal are to determine: (i) the timing of net assembly and disassembly of V-ATPase on endolysosomes and reforming lysosomes; (ii) the mechanism of regulating the net recruitment of the V1 sub-complex of V-ATPase to endolysosomes and its release from reforming lysosomes. To achieve our aims, we will exploit state of the art fluorescence and electron microscopy techniques to study cultured mammalian cells and integrate these cell biology studies with biochemical, biophysical and structural biology techniques. This will enable us to reach our goal of understanding fully the process of V-ATPase assembly/disassembly and its critical role in controlling the lumenal acidity and function of endolysosomes and lysosomes in continuously fed cells. We will then apply the resulting knowledge in a collaboration to understand the role of V-ATPase assembly/disassembly in the specialised case of secretory lysosomes required for the killing function of cytotoxic T lymphocytes (a type of white blood cell). These immune system cells destroy virally infected and cancer cells and are the cornerstone of modern cell-based immunotherapies. Abnormalities of endolysosome/lysosome acidity and function make a major contribution to many disease states including lysosome storage diseases, neurodegeneration and the response to some pathogens. In the long term our work could aid in the identification of potential targets for therapeutic interventions in these diseases. Finally, understanding the regulation of endolysosomal/lysosomal acidification is also important to the pharmaceutical industry because it affects the pharmacokinetics, drug-drug interactions and off-target toxicity of many small molecule drugs. |
| Category | Research and Innovation |
| Reference | MR/Z506011/1 |
| Status | Active |
| Funded period start | 01/01/2025 |
| Funded period end | 31/12/2027 |
| Funded value | £639,516.00 |
| Source | https://gtr.ukri.org/projects?ref=MR%2FZ506011%2F1 |
Participating Organisations
| University of Cambridge |
The filing refers to a past date, and does not necessarily reflect the current state. The current state is available on the following page: University of Cambridge, Cambridge.
