Sharon A. Tooze is a Senior group leader at the London Research Institute Cancer Research UK in London, UK. She obtained her PhD in 1986 from the EMBL, where she worked with Graham Warren in the Cell Biology Programme. During her PhD, she studied the transport and glycosylation of the MHV viral glycoprotein to understand how O-linked glycosylation occurs on integral membrane proteins moving from the ER to the Golgi. During her post-doctoral work with Wieland Huttner at EMBL she expanded her protein trafficking interests to the regulated secretory pathway in neuroendocrine cells.Using cell-free in vitro reconstitution assays she first reconstituted the formation of immature dense-core secretory granules from the Golgi complex, then developed assays to study their maturation into dense-core secretory granules. In 1994, she started her own lab at ICRF in London (now called the London Research Institute) and became a senior group leader in 2002. During this time she showed that biogenesis of secretory granules requires homotypic fusion and subsequent vesicle remodelling, and that the molecular control of these events involved trimeric G-proteins, clathrin coat machinery and SNARE proteins thus providing a greater understanding of how functional exocytic vesicles are made.
In 2003, Sharon Tooze widened her research to investigate mammalian autophagy. Her interest is to understand autophagosome formation at a molecular level. She identified and established, in mammals, the role of several essential early autophagy proteins, including ULK1, Atg13, Atg9, and WIPI2. This was achieved by developing the first siRNA kinome screen in mammalian cells for novel regulators of autophagy, and candidate-based identification of mammalian homologues of the yeast genes. ULK1 is the master kinase controlling autophagy, and she identified an intramolecular regulatory conformation and a membrane targeting domain in this kinase, and a new ULK1 complex member, Atg13. She pioneered the work on mammalian Atg9, the only known membrane protein required for autophagy, by identifying its subcellular trafficking route, and discovering the so-far only known interactor of Atg9, p38IP, which links Atg9 to MAP kinase signalling.
The identification of these proteins has led to insights into their function, and their role in autophagy. Her recent work on the role of RabGAPs and Rab proteins required for starvation-induced autophagy, has lead to the discovery of a pathway controlled by Rab11 from the recycling endosome that delivers ULK1 to the forming autophagosomes. Most recently her lab has carried out the first siGenome wide screen for novel regulators of amino-acid starvation-induced autophagy revealing novel regulators of autophagy which are currently being investigated.
Novel mammalian regulators of starvation-induced autophagy
Autophagy, “self-eating” is a highly conserved cell survival pathway that is essential for cell health and homeostasis. Autophagy also impacts on human diseases, such as cancer and neurodegeneration, as well as on infection and the development of immunity. Autophagy is a membrane-mediated lysosomal degradation process that can be acutely induced by withdrawal of amino acids, and more chronically by lack of growth factors or stressful environmental conditions. Induction by amino acid starvation has been fundamental in the identification of the 30 or more autophagy-related (Atg) genes first in yeast, and more recently in mammals. Starvation-induced autophagy is negatively regulated by mTORC1. ULK1 and ULK2 (mammalian Atg1 homologues) are found in complex with mTORC1 in fed cells and the activity of ULK1/2 kinase is negatively regulated by active mTORC1. Activation of ULK1/2 by inhibition of mTORC1 initiates the formation of autophagsosome precursor membrane structures called isolation membranes or phagophores. At or on these membranes ULK1/2, its complex members FIP200 and Atg13, and at least seven other Atg proteins assemble and together mediate the formation of the double membrane autophagosomes. Autophagosome formation under starvation conditions requires ER-associated membranes and contributions from other organelles, including the Golgi complex. Class III Phosphatidylinositol (PI) 3-kinasecomplex composed of Beclin1, Atg14, Vps34 and p150 is also required for induction of the early precursors, producing an autophagy-specific pool of PI 3 phosphate (PI3P). We are interested in how the autophagosome forms, and undertook two screening approaches to identify new proteins required for starvation-induced autophagy initially using the autophagy marker GFP-LC3. We have identified a RabGAP that mediates ULK1-dependent transport from the recycling endosome to the early autophagosome, and two largely uncharacterized proteins, SCOC and WAC. SCOC is required for autophagy and may provide a link between the ULK1 kinase and PI3P production on the forming autophagosome.
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