Research Spotlight: Understanding How Cells Sense and Respond to the Presence of Nutrients

Max Valenstein, MD, PhD, an investigator in the Department of Medicine’s Physician-Scientist Pathway Residency Program at Massachusetts General Hospital, is co-corresponding author of a new paper in Proceedings of the National Academy of Sciences (PNAS), Rag–Ragulator is the central organizer of the physical architecture of the mTORC1 nutrient-sensing pathway

What Question Were You Investigating with this Study?

Our cells must sense and adapt to constantly changing environmental conditions. When deciding whether to grow, cells pay specific attention to the presence of nutrients including amino acids, which form the building blocks needed to synthesize new proteins. In this project, we studied some of the molecular machines the cell uses to sense and respond to amino acid availability.

More specifically, it is known that the mTORC1 signaling pathway coordinates cellular metabolism with nutrient availability to control cell growth. Nutrients, such as amino acids, signal to mTORC1 through molecular machines (the GATOR1/2 and KICSTOR complexes) that reside on the surface of the lysosome, an organelle that functions as a nutrient recycling center and signaling hub within the cell. We sought to better understand the functional relationship between theses nutrient-sensing complexes and we wanted to know how they are recruited and held onto the lysosome.

What Were the Results?

Our work identifies that these nutrient-sensing protein complexes, which we had initially envisioned as distinct entities, stably assemble together and form an enormous signaling machine, which we call “GATOR,” that conveys the presence of nutrients to the mTORC1 pathway. We also learned that GATOR is held onto the lysosome by the Rag GTPases, which were known to function as molecular switches required for mTORC1 to respond to nutrients.

Our findings highlight the Rag GTPases, and their associated Ragulator complex, as the central actor in both the information transduction and physical architecture of this critical nutrient-sensitive signaling pathway, which evolved specifically to function on the surface of the lysosome.

What are the Next Steps?

This project helps us understand how cells sense and respond to the presence of nutrients, a process that is disrupted in a variety of disease states including cancers, diabetes, and aging. Our results should encourage further exploration of how the GATOR complex works and how the Rag-Ragulator complexes control the lysosome.  Together, this future work may offer new strategies to control cell growth, metabolism, and lysosomal function.


Paper Cited: 
Valenstein, M. L., Lalgudi, P. V., Gu, X., Kedir, J. F., Taylor, M. S., Chivukula, R. R., & Sabatini, D. M. (2024). Rag-Ragulator is the central organizer of the physical architecture of the mTORC1 nutrient-sensing pathway. Proceedings of the National Academy of Sciences of the United States of America, 121(35), e2322755121.https://doi.org/10.1073/pnas.2322755121