Amino Acid Signaling and Growth Control in Yeast
Description: The eukaryotic target of rapamycin complex 1 (TORC1) integrates nutritional, energy, and hormonal signals to homeostatically regulate cellular and organismal growth and metabolism. Underscoring its prime role in these processes, deregulation of TORC1 signaling is often associated with human diseases such as cancer, immunodeficiency, and type 2 diabetes. Among the various inputs that modulate the activity of TORC1, amino acids are particularly important as they represent primordial stimuli that cannot be compensated for by any other signals. Amino acid levels are communicated to TORC1 through the GTP-/GDP-loading status of the heterodimeric Rag GTPases, which function within larger complexes coined Ragulator-Rag GTPase in mammals or EGO complex (EGOC) in yeast and which appear to predominately act on lysosomal surfaces. Studies in various model systems have identified multiple proximal Rag GTPase regulatory modules (e.g., GAPs and GEFs) and specific amino acid sensors acting upstream of these modulators, but how these sensory modules impact spatially, temporally, and mechanistically on the Rag GTPase regulators remains largely mysterious. Equally important and still mostly elusive are the feedback circuits by which TORC1 controls Rag GTPases to maintain cellular homeostasis. Building on our previous Rag GTPase-centered work in yeast, including our recent discovery of two spatially distinct endosomal and vacuolar pools of TORC1 that impinge on functionally divergent effectors, we propose here a series of experimental approaches that address some of the most pertinent and pending questions in the field. Accordingly, we plan to further explore the architecture, local regulation, and effector targeting of the endosomal and vacuolar TORC1 assemblies, to pinpoint critical amino acid sensors that feed into the EGOC-TORC1 signaling branch, and to elucidate the regulatory loops that emanate from TORC1 to feedback control the Rag GTPases. Given the remarkably high conservation of many aspects of the Rag GTPase-mediated control of TORC1, our studies will likely be both valuable for our understanding of human pathologies caused by abnormal TORC1 signaling and conducive for the development of therapeutic approaches that rationally target TORC1-related diseases.
Amount: CHF 846,700
Funding type: research
Funder scheme: Project funding
Start date: 2019-08-01
End date: 2023-07-31
Investigator: De Virgilio, Claudio
Institution: University of Fribourg – FR
Subfield: Molecular Biology
Domain: Life Sciences
Funded outputs count: 18
Funder award ID: 184671
OpenAlex ID: G7763750272