Regulation of autophagy by mTORC1 and ULK1

Doubleday, Peter 2015. Regulation of autophagy by mTORC1 and ULK1. MPhil Thesis, Cardiff University. Item availability restricted.

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Abstract

Macroautophagy is a catabolic cellular process responsible for bulk degradation of proteins. Largely conserved from yeast to mammals, the initiating steps of autophagy and key signalling proteins governing the complex biological process have been initially characterised. However, very little is known of one critical protein kinase, ULK1, which is thought to govern the induction of autophagy. ULK1 is regulated by two upstream kinases, via energy sensing through AMPK and nutrient sensing through mTORC1. While several studies have identified ULK1 binding partners in cells, the list of functional interactions remains limited. Further, as an enzyme, the targets of ULK1 and the possibility of a consensus phosphorylation motif remains largely unknown. Herein, using a phosphoproteomic screen and purification approaches, we identify new ULK1 protein interactions and ULK1-mediated phosphorylation events. A novel ULK1 kinase inhibitor is also initially characterised, which potently blocks ULK1 phosphotransfer to downstream substrates and itself, and autophagosomal maturation in mammalian cells. Furthermore, examining a known ULK1 binding partner, FLCN, we explore novel molecular aspects of a rare genetic disease, Birt-Hogg-Dubé syndrome and its connection as a ciliopathy.

Item Type:	Thesis (MPhil)
Date Type:	Completion
Status:	Unpublished
Schools:	Medicine
Subjects:	R Medicine > R Medicine (General)
Date of First Compliant Deposit:	30 March 2016
Last Modified:	13 Jun 2022 16:02
URI:	https://orca.cardiff.ac.uk/id/eprint/80621

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