Supervisor Project : Dynamic Ub modification regulated and interpreted by endosomal sorting complexes
Sylvie Urbé was born and educated in Luxembourg, studied Biology at the University of Heidelberg and worked at the European Molecular Biology Laboratory on vesicular traffic and Rab GTPases. She was awarded a PhD from University College London for her study of the regulated secretory pathway in neuroendocrine cells at the Imperial Cancer Research Fund in London. Her post-doctoral work was focussed on endosomal sorting (ESCRT, HGS/HRS) and led on to a series of Wellcome Trust and Cancer Research UK funded Fellowships supporting her work on the regulation of receptor trafficking and signalling by deubiquitylases (DUBs). She now holds a professorial chair at the University of Liverpool, where she works closely together with Michael Clague, studying the cell biology of this family of enzymes and exploring their potential as therapeutic drug targets.
We seek to understand the modes of Ub chain recognition and editing associated with endo-lysosomal degradative pathways. The ESCRT-0 complex (HRS and STAM) engages ubiquitylated growth factor receptors for lysosomal sorting via five Ub binding domains, which combine to provide a unique topology for Ub chain interactions. We propose to leverage stable cell lines we either have already made or will generate to identify ubiquitylated proteins interacting with GFP or APEX-tagged HRS/STAM and profile the preferred chain types that associate with the ESCRT-0 complex ± growth factors. We will also immunoisolate intact endosomes or use APEX mediated biotinylation to profile the endosomal ubiquitylation landscape. Finally we will examine the influence of endosome associated de-ubiquitylases (DUBs) with differing chain specificities for their influence upon ESCRT capture of receptors, ESCRT-0 associated chain types and the endosome associated Ub profile.