Amino acid signaling and growth control in yeast
Description: The target of rapamycin complex 1 (TORC1) plays a central role in the control of eukaryotic cell growth by fine-tuning anabolic and catabolic processes to the nutritional status of organisms and individual cells. Deregulation of this pathway in humans is associated with a number of pathological conditions, including cancer, obesity, and type 2 diabetes. Amino acids represent essential and primordial signals that modulate TORC1 activity through the conserved Rag family GTPases, which assemble, as part of the lysosomal/vacuolar membrane-associated mammalian Rag-Ragulator or yeast EGO complexes, into heterodimeric sub-complexes consisting of mammalian RagA or RagB and RagC or RagD, or yeast Gtr1 and Gtr2. The TORC1-stimulating state of these heterodimers contains GTP-bound RagA/B/Gtr1 and GDP-bound RagC/D/Gtr2, and is maintained by various guanine nucleotide exchange factor (GEF) and GTPase-activating (GAP) protein complexes, which are also remarkably conserved (such as for instance the heterotrimeric RagA/B- and Gtr1-GAP complexes coined GATOR1 and SEACIT, or the heterodimeric RagC/D- and Gtr2-GAP complexes termed FNIP-Folliculin and Lst4-Lst7, respectively). The amino-acid sensitive events upstream of these Rag GTPase regulators are still poorly understood, but likely involve both lysosomal amino acid sensors, such as the v-ATPase and lysosomal amino acid transporter(s), and cytoplasmic amino acid sensors such as the leucyl-tRNA synthetase (LeuRS). Here, we propose to build on and continue our previous Rag GTPase-centered research in yeast to address some of the most pertinent and outstanding questions in this field. Accordingly, we intend (i) to further refine our understanding of the architecture of the Rag GTPase containing EGO complex (EGOC), (ii) to complete the repertory of Rag GTPase regulators, (iii) to identify the respective amino acid-controlled mechanisms that impinge on these regulators, and (iv) to address the molecular mechanism by which Rag GTPases regulate TORC1 in yeast. Given the importance of TORC1 in eukaryotic cell growth control, answers to these questions will not only be interesting for our understanding of basic mechanisms in signal transduction, but also provide insight into the human pathologies that are triggered by TORC1 deregulation.
Amount: CHF 756,000
Funding type: research
Funder scheme: Project funding
Start date: 2016-08-01
End date: 2019-07-31
Investigator: De Virgilio, Claudio
Institution: University of Fribourg – FR
Funded outputs count: 14
Funder award ID: 166474
OpenAlex ID: G1780931065