Research Project 2:
Regulation of TMEM55A/B-dependent positioning of lysosomes
Principal Investigator
PhD Student (FOR2625 funded)
Valentin Duhay, MSc
Project Summary
Lysosomes are highly dynamic organelles. Their spatio-temporal distribution within a cell depends on active transport mainly driven by microtubule motors such as kinesins and dynein and the interaction of motor proteins with cargoes is mediated by a sophisticated system of membrane-proteins present on cargo vesicles. TMEM55B, a lysosomal double-spanning transmembrane protein with a large cytosolic domain, is such a protein that mediates motor-protein interaction and thereby regulates lysosomal positioning. We plan to validate TMEM55B and TMEM55A-interacting proteins, previously identified by co-immunoprecipitation and mass spectroscopy and determine their contribution on intracellular sorting of TMEM55A and TMEM55B and lysosomal positioning. Finally we plan to investigate the dependence of different posttranslational modifications of TMEM55B we determined previously on each other and on cellular trafficking of TMEM55B and lysosomal positioning. In summary, our experiments will provide a detailed understanding of TMEM55B on lysosomal positioning with an emphasis on neuronal transport and possible other, positioning independent, functions in vitro and in vivo.
References
Lüningschrör P, Werner G, Stroobants S, Kakuta S, Dombert B, Sinske D, Wanner R, Lüllmann-Rauch R, D’Hooge R, Uchiyama Y, Sendtner M, Haass C, Saftig P, Knöll B, Capell A, Damme M. The FTLD risk factor TMEM106B regulates the transport of lysosomes at the axon initial segment of motoneurons. Cell Rep 2020; 30:3506-19.e6.
Gonzalez AC, Schweizer M, Jagdmann S, Bernreuther C, Reinheckel T, Saftig P, Damme M. Unconventional Trafficking of Mammalian Phospholipase D3 to Lysosomes. Cell Rep 2018; 22:1040-53.
Varga RE, Khundadze M, Damme M, Nietzsche S, Hoffmann B, Stauber T, Koch N, Hennings JC, Franzka P, Huebner AK, Kessels MM, Biskup C, Jentsch TJ, Qualmann B, Braulke T, Kurth I, Beetz C, Hübner CA. In Vivo Evidence for Lysosome Depletion and Impaired Autophagic Clearance in Hereditary Spastic Paraplegia Type SPG11. PLoS Genet 2015; 11:e10054.