Sestrin2 inhibits mTORC1 through modulation of GATOR complexes

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

doi:10.1038/srep09502

Sestrin2 inhibits mTORC1 through modulation of GATOR complexes

Journal Article · Mon Mar 30 00:00:00 EDT 2015 · Scientific Reports

DOI:https://doi.org/10.1038/srep09502· OSTI ID:1351363

Kim, Jeong Sig ^[1]; Ro, Seung-Hyun ^[2]; Kim, Myungjin ^[2]; Park, Hwan-Woo ^[2]; Semple, Ian A. ^[2]; Park, Haeli ^[2]; Cho, Uhn-Soo ^[2]; Wang, Wei ^[3]; Guan, Kun-Liang ^[3]; Karin, Michael ^[3]; Lee, Jun Hee ^[2]

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)

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.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: American Association for the Study of Liver Diseases/American Liver Foundation; American Diabetes Association; Ellison Medical Foundation; National Inst. of Health

OSTI ID:: 1351363

Journal Information:: Scientific Reports, Journal Name: Scientific Reports Journal Issue: 1 Vol. 5; ISSN 2045-2322

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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