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Functional analysis of SCOC and FEZ proteins in autophagy using mammalian cell models and zebrafish (SCOC and FEZ)
Start date: Apr 1, 2013, End date: Mar 31, 2015 PROJECT  FINISHED 

Autophagy is a conserved, highly regulated degradative pathway transferring cytoplasmic components in autophagosomes to lysosomes providing energy for cellular metabolism. In multicellular organisms autophagy is essential for tissue homeostasis and deficient autophagy is implicated in a broad range of diseases e.g. cancer and neurodegenerative disorders. To develop therapeutic strategies targeting autophagy a comprehensive understanding of the molecular protein machinery mediating and regulating autophagy is required.In a genome wide siRNA screen the host laboratory identified SCOC, a small Golgi protein, as a novel positive regulator of starvation-induced autophagosome formation. SCOC forms a complex with FEZ1, which also contains ULK1. FEZ1 negatively regulates autophagy and FEZ1 and the related FEZ2 associate with ULK1 and mTORC1 kinase complexes. The TOR signalling pathway is central in nutrient sensing. Starvation inactivates mTOR kinase leading to ULK kinase activation and autophagy induction. SCOC and FEZ also interact with the tumor suppressor UVRAG, a subunit of class III Beclin1-PI(3)K lipid kinase complexes essential for autophagy induction and progression. Autophagy is crucial for nervous system development and neuronal survival. Interestingly, SCOC and FEZ1 are highly expressed in neurons and required for axon elongation in C. elegans.I hypothesize that SCOC and FEZ are membrane-proximal scaffold and adapter proteins important in regulating and coordinating the three key autophagic signalling complexes, mTORC1, ULK1 and UVRAG-Beclin1-PI(3)K. I aim to understand the molecular details of this function and how they relate to vertebrate nervous system development and homeostasis. Our multidisciplinary approach (biochemistry, biophysics, cell biology, imaging and zebrafish techniques) characterizing SCOC and FEZ function may also impact development of new therapeutic strategies in targeting autophagy in disease.
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