# The molecular mechanisms of nutrient- and stress-dependent mTORC1 regulation mediated by human Sestrin2.

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $472,784

## Abstract

Title: The molecular mechanisms of nutrient- and stress-dependent
mTORC1 regulation mediated by human Sestrin2.
Project Summary
 The mTOR complex 1 (mTORC1) is an important nutrient sensor whose chronic
activation by overnutrition can provoke diverse metabolic pathologies such as insulin
resistance and type II diabetes. Most pharmacological inhibitors of mTORC1, however,
non-specifically suppress mTORC2—another mTOR complex that is critical for
mediating insulin signal transduction—and thus inappropriate for diabetes treatment.
 Sestrins (Sesns) are recently identified mTORC1 suppressors. mTORC1-inhibitory
function of Sesns attenuates development of most hypernutrition- and obesity-
associated metabolic pathologies. Importantly, Sesns does not inhibit mTORC2 and
rather upregulates its activity by suppressing mTORC1. Correspondingly, transgenic
Sesn overexpression was highly effective in protecting liver from chronic mTORC1
activation, development of insulin resistance and progression of diabetic pathologies.
These results suggest that Sesns and their downstream signaling pathway may have a
therapeutic potential as a drug target toward the obesity-associated diseases.
 Recently, a number of studies by our labs and others have clarified the molecular
targets of Sesns, which led to a clearer understanding of how Sesns inhibit mTORC1. As
a result of extensive genetics and cell biology studies, a clear epistatic relationship
between GATOR2, GATOR1, Rag GTPases and mTORC1 was established.
Furthermore, a couple of recent papers also suggested that an amino acid leucine can
bind to Sesns and modulates their activities.
 Despite its physiological significance, the biochemical and molecular basis by which
these proteins interact with and signal to each other is still completely unknown. Without
an understanding of the molecular level mechanism, it is nearly impossible to rationally
design chemical probes to modulate this signaling cascade. As a part of this effort, we
have recently determined the first crystal structure of human Sestrin2 (hSesn2), and are
currently planning to use it as a starting platform for understanding the Sesn-dependent
signal transduction pathway. Our long-term goal is to define the biochemical and
structural properties of each signaling component within the Sesn-dependent signaling
cascade and to reveal druggable structural motifs that are critical for functionality of this
signaling pathway. Using a combination of X-ray crystallography, molecular electron
microscopy (EM), cell biology and Drosophila/mouse genetics experiments, we will
elucidate the structural, biochemical and cell-biological role of hSesn2 and its signaling
intermediates—GATOR1 and GATOR2—in mTORC1 suppression. The molecular
mechanisms and structural motifs identified from these studies are expected to reveal
many new drug targets for future development of mTORC1-modulating pharmaceutical
agents, which will be clinically significant for reducing the progression of...

## Key facts

- **NIH application ID:** 9996571
- **Project number:** 5R01DK111465-05
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Uhn-Soo Cho
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $472,784
- **Award type:** 5
- **Project period:** 2016-09-19 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9996571

## Citation

> US National Institutes of Health, RePORTER application 9996571, The molecular mechanisms of nutrient- and stress-dependent mTORC1 regulation mediated by human Sestrin2. (5R01DK111465-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9996571. Licensed CC0.

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