Eukaryotic growth is regulated by TOR, a kinase that is activated by amino acids and glucose and then broadly promotes anabolism, including protein, lipid, and nucleotide synthesis. TOR dysregulation causes or contributes to an array of human diseases, including cancer, obesity, viral infections, diabetes, aging, and neurodegeneration. TOR signaling is under intense investigation among yeast and animal cell biologists, who seek to characterize the mechanisms that control TOR signaling networks in order to develop treatments to fine-tune TOR activity as therapies for human diseases. Much less is known about the TOR signaling network in the other major eukaryotic lineage, plants. This project uses a combination of genetic, biochemical, genomic, and proteomic approaches to pursue my recent groundbreaking discovery of an amino acid sensor that activates TOR in plant cells. No amino acid sensors have been previously characterized in plants, although amino acids are the primary form of nitrogen found in many natural soils, and amino acids are the primary transported form of nitrogen between organs in most plant species. Understanding how plants sense and respond to nitrogen is a top priority for plant molecular biologists, because global crop yields rely massively on heavy use of environmentally-harmful and expensive petrochemical fertilizers. This proposed investigation of a nitrogen sensor that activates TOR will enable intelligent breeding efforts to produce crops that are able to generate high crop yields in low nitrogen environments by modulating plants' nitrogen sensing mechanisms. The first specific aim of this project is to first determine how nitrogen sources affect TOR activity, and then to confirm that the proposed amino acid sensor, an aminoacyl tRNA synthetase, does act upstream of TOR signaling.
The second aim of this project is to use powerful contemporary proteomic techniques to identify proteins that interact with TOR and/or the proposed nitrogen sensor to control nitrogen-mediated TOR activation using powerful proteomic techniques. Finally, the role of the proposed nitrogen sensor in plant development, crop yields, and responses to environmental nitrogen sources will be explored in several of the most important global crop species. With this innovative approach to exploring how amino acid sensing mechanisms have evolved with TOR signaling in eukaryotes, this project will simultaneously advance understanding of how plants coordinate growth and development with nitrogen availability, and provide original insights into amino acid-TOR networks that will benefit biomedical studies of TOR cell biology in humans.
TOR is a central regulatory kinase that coordinates growth with amino acid availability in eukaryotes, and TOR dysregulation contributes to a range of diseases including cancer, diabetes, and neurodegeneration, but the roles of putative amino acid sensors that might control TOR activity in humans are currently under debate. I have identified the first putative amino acid sensor in plants, an aminoacyl tRNA synthetase that stimulates TOR in response to amino acids, which is analogous to one of the putative human amino acid sensors upstream of TOR, leucyl tRNA synthetase. This project will contribute to efforts to fine-tune nitrogen sensing in crops in order to curtail use of environmentally-harmful petrochemical fertilizers, and place the ongoing investigation of possible human amino acid sensors into the context of eukaryotic evolution.
| Brunkard, Jacob O; Burch-Smith, Tessa M (2018) Ties that bind: the integration of plastid signalling pathways in plant cell metabolism. Essays Biochem 62:95-107 |
