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Albert Haas (2011-2017)

(joint project with Paul Saftig) Lysosomal Membrane Proteins and their Roles in Phagosome Maturation

Lysosomes play a central role in many cellular events ranging from uptake and degradation of plasma membrane receptors and extracellular components to autophagy, infection with viruses, membrane repair, and killing and degradation of phagocytosed microorganisms. The abundance and distribution of integral and associated lysosome membrane proteins regulate lysosome acidification, transport of metabolites and ions across the membrane, the acquisition of newly produced lysosome hydrolases and the fusion processes between lysosomes and late endosomes, late phagosomes and autophagosomes. How lysosome membrane proteins mediate fusion between late endocyticcompartments and phagosomes remains an unsolved question. Our studies in the first funding period demonstratedhe essential role of LAMP-proteins in regulating lysosome motility and, indirectly, lysosome fusion with phagosomes, but did not support a direct role of LAMP (lysosome-associated membrane proteins)-1 and -2, LIMP-(lysosome integral membrane protein) -2, or CD63/LIMP-1 in the fusion process of lysosomes with phagosomes. We have further investigated the possible involvement of the proton-pumping vacuolar (v-)ATPase as a fusion-regulating entity, based onprevious reports that v-ATPase subunits modulate fusion between various membranes directly. We analysed the phagocytic and endocytic pathways in cells derived from mice which lack the a3-subunitof vATPase or the accessory subunit ATP6AP2 which leads to almost complete loss of vATPase. In all cases, phagosome-lysosome fusion progressed almost normally. We will finalise the characterization of the role of the mammalian v-ATPase in phagosome maturation. Furthermore, we plan to extend our efforts to understand how lysosome transmembrane calcium transporters contribute to fusion with phagosomes. This will be done using various pharmacological calcium channel inhibitors, siRNA technology, knockout animal cells, kinetic microscopy analysis and in cellulo- as well as in vitro-characterisation of fusion competences. Taken together, our experiments will shed light on how lysosome membrane proteins are molecularly involved in regulation and catalysis of phagolysosome biogenesis and may provide new pharmacological angles to fight off certain infectious diseases.

 

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