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Title: Sestrin2 inhibits mTORC1 through modulation of GATOR complexes

Abstract

Sestrins are stress-inducible metabolic regulators that suppress a wide range of age- and obesity-associated pathologies, many of which are due to mTORC1 overactivation. Upon various stresses, the Sestrins inhibit mTORC1 activity through an indirect mechanism that is still unclear. GATORs are recently identified protein complexes that regulate the activity of RagB, a small GTPase essential for mTORC1 activation. GATOR1 is a GTPase activating protein (GAP) for RagB whereas GATOR2 functions as an inhibitor of GATOR1. However, how the GATORs are physiologically regulated is unknown. Here we show that Sestrin2 binds to GATOR2, and liberates GATOR1 from GATOR2-mediated inhibition. Released GATOR1 subsequently binds to and inactivates RagB, ultimately resulting in mTORC1 suppression. Consistent with this biochemical mechanism, genetic ablation of GATOR1 nullifies the mTORC1-inhibiting effect of Sestrin2 in both cell culture and Drosophila models. Collectively, we elucidate a new signaling cascade composed of Sestrin2-GATOR2-GATOR1-RagB that mediates stress-dependent suppression of mTORC1 activity.

Authors:
; ; ; ; ; ; ; ; ; ;
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
National Institutes of Health (NIH)
OSTI Identifier:
1351363
Resource Type:
Journal Article
Journal Name:
Scientific Reports
Additional Journal Information:
Journal Volume: 5; Journal Issue: 1; Journal ID: ISSN 2045-2322
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES

Citation Formats

Kim, Jeong Sig, Ro, Seung-Hyun, Kim, Myungjin, Park, Hwan-Woo, Semple, Ian A., Park, Haeli, Cho, Uhn-Soo, Wang, Wei, Guan, Kun-Liang, Karin, Michael, and Lee, Jun Hee. Sestrin2 inhibits mTORC1 through modulation of GATOR complexes. United States: N. p., 2015. Web. doi:10.1038/srep09502.
Kim, Jeong Sig, Ro, Seung-Hyun, Kim, Myungjin, Park, Hwan-Woo, Semple, Ian A., Park, Haeli, Cho, Uhn-Soo, Wang, Wei, Guan, Kun-Liang, Karin, Michael, & Lee, Jun Hee. Sestrin2 inhibits mTORC1 through modulation of GATOR complexes. United States. doi:10.1038/srep09502.
Kim, Jeong Sig, Ro, Seung-Hyun, Kim, Myungjin, Park, Hwan-Woo, Semple, Ian A., Park, Haeli, Cho, Uhn-Soo, Wang, Wei, Guan, Kun-Liang, Karin, Michael, and Lee, Jun Hee. Mon . "Sestrin2 inhibits mTORC1 through modulation of GATOR complexes". United States. doi:10.1038/srep09502.
@article{osti_1351363,
title = {Sestrin2 inhibits mTORC1 through modulation of GATOR complexes},
author = {Kim, Jeong Sig and Ro, Seung-Hyun and Kim, Myungjin and Park, Hwan-Woo and Semple, Ian A. and Park, Haeli and Cho, Uhn-Soo and Wang, Wei and Guan, Kun-Liang and Karin, Michael and Lee, Jun Hee},
abstractNote = {Sestrins are stress-inducible metabolic regulators that suppress a wide range of age- and obesity-associated pathologies, many of which are due to mTORC1 overactivation. Upon various stresses, the Sestrins inhibit mTORC1 activity through an indirect mechanism that is still unclear. GATORs are recently identified protein complexes that regulate the activity of RagB, a small GTPase essential for mTORC1 activation. GATOR1 is a GTPase activating protein (GAP) for RagB whereas GATOR2 functions as an inhibitor of GATOR1. However, how the GATORs are physiologically regulated is unknown. Here we show that Sestrin2 binds to GATOR2, and liberates GATOR1 from GATOR2-mediated inhibition. Released GATOR1 subsequently binds to and inactivates RagB, ultimately resulting in mTORC1 suppression. Consistent with this biochemical mechanism, genetic ablation of GATOR1 nullifies the mTORC1-inhibiting effect of Sestrin2 in both cell culture and Drosophila models. Collectively, we elucidate a new signaling cascade composed of Sestrin2-GATOR2-GATOR1-RagB that mediates stress-dependent suppression of mTORC1 activity.},
doi = {10.1038/srep09502},
journal = {Scientific Reports},
issn = {2045-2322},
number = 1,
volume = 5,
place = {United States},
year = {2015},
month = {3}
}

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