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Title: Roles of the ESCRT machinery in endosomal sorting and the regulation of cytokinetic abscission
Author: Caballe Ibañez, Anna
ISNI:       0000 0004 7656 0792
Awarding Body: King's College London
Current Institution: King's College London (University of London)
Date of Award: 2014
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The Endosomal Sorting Complex Required for Transport (ESCRT) machinery is directly involved in facilitating scission of topologically equivalent membrane tethers, namely the release of cargo-filled vesicles into multivesicular bodies (MVBs), the budding of viral particles from infected cells and abscission of the intercellular bridge (midbody) connecting dividing cells. The core ESCRT-III proteins assemble into functional filament-like structures to promote membrane scission activity. While the activity of ESCRT-III is crucial for all ESCRT-mediated functions, recent studies have started to shed light onto the differential requirements amongst ESCRT subunits and associated proteins in each of the processes mediated by the ESCRT scission machinery. Nevertheless, the existence of mechanisms providing functional specificity within the pathway is still poorly understood. Current efforts focus on understanding the spatiotemporal distribution and regulation of the ESCRT machinery, particularly during cytokinetic abscission, in which membrane scission needs to be precisely timed with chromosome segregation. The work I present in this thesis uncovers mechanisms of specificity and regulation of the ESCRT machinery. We demonstrate the specific role in endosomal sorting of ubiquitin-associated protein 1 (UBAP1), a newly identified ESCRT-I subunit. In addition, we describe the interactions of ESCRT-III with Unc-51-like kinase 3 (ULK3) and MIT domain-containing protein 1 (MITD1), revealing their specific functions in cytokinesis and the regulation of midbody abscission. Further work is presented arising from our recent findings connecting the abscission checkpoint pathway (NoCut) with the ESCRT machinery, via the ESCRT-III subunit CHMP4C, to coordinate chromosome segregation with abscission. Specifically, the data presented here demonstrate that ULK3 modulates abscission timing via its kinase activity and interactions with ESCRT-III. Furthermore, we identify ULK3 as an essential component of the NoCut pathway, which is functionally interconnected with CHMP4C. Moreover, a role for ULK3 in tension-dependent abscission regulation is described, suggesting its function as a general modulator of abscission timing.
Supervisor: Martin Serrano, Juan ; Neil, Stuart John Douglas Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available