The mTORC1 kinase complex is a major regulator of cell growth and metabolism and is deregulated in common human diseases such as diabetes and cancer. Therefore, understanding the normal regulation of mTORC1 is of great importance to guide therapies for these diseases. We have discovered a novel input into the mTOR pathway that involves aspartate sensing. Interestingly, aspartate biosynthesis requires intact mitochondrial electron transport chain function suggesting that aspartate provides a previously unrecognized link from mitochondrial function to the mTOR pathway. Like sensing of other amino acids in the mTOR pathway we find that aspartate is sensed upstream of the Rag-GTPases. However, the identity of an aspartate sensor and how aspartate sufficiency signals to the Rags remains entirely unknown. The goal of this project is to determine the mechanism of aspartate sensing by the mTOR pathway. To that end, we propose the following aims: 1. Establish which pathway upstream of the Rag-GTPases signals aspartate sufficiency to mTORC1. 2. Identify proteins involved in signaling aspartate sufficiency to mTORC1. 3. Determine whether proteins identified in aim 2 are direct aspartate sensors. By taking both hypothesis driven and unbiased approaches, our proposed work will describe a new input into the mTOR pathway. Our results may also provide a new mechanism that explains the link between drugs that target the electron transport chain, such as metformin, and the mTOR pathway.
We have found that the amino acid aspartate is sensed by the mTOR pathway, which is known to integrate many signals including amino acid availability to regulate cell growth and metabolism. Interestingly, aspartate is only made in cells with intact mitochondrial electron transport chain and therefore it provides a link between mitochondrial function and mTOR signaling. The goal of the project is to elucidate the mechanism of aspartate sensing by the mTOR pathway.
|Wolfson, Rachel L; Chantranupong, Lynne; Wyant, Gregory A et al. (2017) KICSTOR recruits GATOR1 to the lysosome and is necessary for nutrients to regulate mTORC1. Nature 543:438-442|
|Gu, Xin; Orozco, Jose M; Saxton, Robert A et al. (2017) SAMTOR is an S-adenosylmethionine sensor for the mTORC1 pathway. Science 358:813-818|