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:
-
- Univ. of Michigan, Ann Arbor, MI (United States); Soonchunhyang Univ. Seoul Hospital, Seoul (Korea)
- Univ. of Michigan, Ann Arbor, MI (United States)
- Univ. of California, San Diego, CA (United States)
- Publication Date:
- Research Org.:
- Argonne National Laboratory (ANL), Argonne, IL (United States)
- Sponsoring Org.:
- National Inst. of Health; American Association for the Study of Liver Diseases/American Liver Foundation; American Diabetes Association; Ellison Medical Foundation
- OSTI Identifier:
- 1351363
- Grant/Contract Number:
- P30AG024824; P30AG013283; P30DK020572; P30DK034933; P30DK089503; P30CA046592; R21AG045432; 1-13-BS-106; AG-NS-0932-12
- Resource Type:
- Accepted Manuscript
- 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. https://doi.org/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. https://doi.org/10.1038/srep09502. https://www.osti.gov/servlets/purl/1351363.
@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},
number = 1,
volume = 5,
place = {United States},
year = {Mon Mar 30 00:00:00 EDT 2015},
month = {Mon Mar 30 00:00:00 EDT 2015}
}
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