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The RabGAP TBC1D14 regulates autophagosome formation via recycling endosomes and Rab11

Longatti, A.D.; (2010) The RabGAP TBC1D14 regulates autophagosome formation via recycling endosomes and Rab11. Doctoral thesis , UCL (University College London). Green open access

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Autophagy is a bulk degradation process characterised by the formation of double membrane vesicles called autophagosomes. Autophagosomes derive from a small precursor structure called phagophore, which is expanded to enclose a portion of cytoplasm or organelle, and finally fuses with the endo-lysosomal system to acquire degradative capacity. Autophagy is often studied as a response to starvation, since the degraded components can be re-used for biosynthetic pathways. However, in multicellular organisms, it has many additional functions in tissue homeostasis, during development, in infection and immunity, and in programmed cell death. Regarding autophagy many questions remain such as the origin of the autophagosomal membrane, the mechanism of phagophore extension and many of the signalling pathways that lead to autophagosome assembly. To better understand the membrane trafficking events involved in autophagosome formation I did an over-expression screen for Rab GTPase activating proteins (RabGAPs) inhibiting this process. RabGAPs act inhibitory on Rab GTPases, which are major regulators of intracellular membrane traffic. I have identified 11 RabGAPs that inhibit autophagosome formation, one of which is TBC1D14, which binds to ULK1, an important kinase for initiation of autophagy. TBC1D14 also binds to Rab11 and tubulates recycling endosomes when over-expressed. I found that both ULK1 and another essential autophagy protein mAtg9 localise to recycling endosomes under normal conditions. I propose that recycling endosomes can signal through both ULK1 and mAtg9 to initiate autophagosome formation upon starvation and may be important in monitory cellular nutrient status, and/or provide membrane to autophagosomes. Investigating the role of ULK1 in vivo, I found that ULK1 knock-out mice are able to undergo basal autophagy as assessed by LC3 lipidation in various tissues. However, ULK1 knock-out mice have less CD4 and CD8-positive mature T cells and their response to TCR stimulation is impaired compared to T cells from wild type animals.

Type: Thesis (Doctoral)
Title: The RabGAP TBC1D14 regulates autophagosome formation via recycling endosomes and Rab11
Open access status: An open access version is available from UCL Discovery
Language: English
UCL classification: UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
URI: https://discovery.ucl.ac.uk/id/eprint/642300
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