Sestrins Inhibit mTORC1 Kinase Activation through the GATOR Complex
Anita Parmigiani,
Aida Nourbakhsh,
Boxiao Ding,
Wei Wang,
Young Chul Kim,
Konstantin Akopiants,
Kun-Liang Guan,
Michael Karin,
Andrei V. Budanov
Affiliations
Anita Parmigiani
Department of Human and Molecular Genetics, Goodwin Research Laboratories, Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA
Aida Nourbakhsh
Department of Human and Molecular Genetics, Goodwin Research Laboratories, Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA
Boxiao Ding
Department of Human and Molecular Genetics, Goodwin Research Laboratories, Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA
Wei Wang
Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093, USA
Young Chul Kim
Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093, USA
Konstantin Akopiants
Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA 23298, USA
Kun-Liang Guan
Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093, USA
Michael Karin
Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093, USA
Andrei V. Budanov
Department of Human and Molecular Genetics, Goodwin Research Laboratories, Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA
The mechanistic target of rapamycin complex 1 (mTORC1) kinase is a sensor of different environmental conditions and regulator of cell growth, metabolism, and autophagy. mTORC1 is activated by Rag GTPases, working as RagA:RagB and RagC:RagD heterodimers. Rags control mTORC1 activity by tethering mTORC1 to the lysosomes where it is activated by Rheb GTPase. RagA:RagB, active in its GTP-bound form, is inhibited by GATOR1 complex, a GTPase-activating protein, and GATOR1 is in turn negatively regulated by GATOR2 complex. Sestrins are stress-responsive proteins that inhibit mTORC1 via activation of AMP-activated protein kinase (AMPK) and tuberous sclerosis complex. Here we report an AMPK-independent mechanism of mTORC1 inhibition by Sestrins mediated by their interaction with GATOR2. As a result of this interaction, the Sestrins suppress mTOR lysosomal localization in a Rag-dependent manner. This mechanism is potentially involved in mTORC1 regulation by amino acids, rotenone, and tunicamycin, connecting stress response with mTORC1 inhibition.
