The Sestrins Interact with GATOR2 to Negatively Regulate the Amino-Acid-Sensing Pathway Upstream of mTORC1
Lynne Chantranupong,
Rachel L. Wolfson,
Jose M. Orozco,
Robert A. Saxton,
Sonia M. Scaria,
Liron Bar-Peled,
Eric Spooner,
Marta Isasa,
Steven P. Gygi,
David M. Sabatini
Affiliations
Lynne Chantranupong
Department of Biology, Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology, 9 Cambridge Center, Cambridge, MA 02142, USA; Department of Biology, Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Koch Institute for Integrative Cancer Research, 77 Massachusetts Avenue, Cambridge, MA 02139, USA; Broad Institute of Harvard and Massachusetts Institute of Technology, 7 Cambridge Center, Cambridge MA 02142, USA
Rachel L. Wolfson
Department of Biology, Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology, 9 Cambridge Center, Cambridge, MA 02142, USA; Department of Biology, Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Koch Institute for Integrative Cancer Research, 77 Massachusetts Avenue, Cambridge, MA 02139, USA; Broad Institute of Harvard and Massachusetts Institute of Technology, 7 Cambridge Center, Cambridge MA 02142, USA
Jose M. Orozco
Department of Biology, Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology, 9 Cambridge Center, Cambridge, MA 02142, USA; Department of Biology, Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Koch Institute for Integrative Cancer Research, 77 Massachusetts Avenue, Cambridge, MA 02139, USA; Broad Institute of Harvard and Massachusetts Institute of Technology, 7 Cambridge Center, Cambridge MA 02142, USA
Robert A. Saxton
Department of Biology, Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology, 9 Cambridge Center, Cambridge, MA 02142, USA; Department of Biology, Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Koch Institute for Integrative Cancer Research, 77 Massachusetts Avenue, Cambridge, MA 02139, USA; Broad Institute of Harvard and Massachusetts Institute of Technology, 7 Cambridge Center, Cambridge MA 02142, USA
Sonia M. Scaria
Department of Biology, Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology, 9 Cambridge Center, Cambridge, MA 02142, USA; Department of Biology, Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
Liron Bar-Peled
Department of Biology, Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology, 9 Cambridge Center, Cambridge, MA 02142, USA; Department of Biology, Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Koch Institute for Integrative Cancer Research, 77 Massachusetts Avenue, Cambridge, MA 02139, USA; Broad Institute of Harvard and Massachusetts Institute of Technology, 7 Cambridge Center, Cambridge MA 02142, USA
Eric Spooner
Department of Biology, Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology, 9 Cambridge Center, Cambridge, MA 02142, USA
Marta Isasa
Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115, USA
Steven P. Gygi
Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115, USA
David M. Sabatini
Department of Biology, Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology, 9 Cambridge Center, Cambridge, MA 02142, USA; Department of Biology, Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Koch Institute for Integrative Cancer Research, 77 Massachusetts Avenue, Cambridge, MA 02139, USA; Broad Institute of Harvard and Massachusetts Institute of Technology, 7 Cambridge Center, Cambridge MA 02142, USA; Corresponding author
Summary: The mechanistic target of rapamycin complex 1 (mTORC1) kinase is a major regulator of cell growth that responds to numerous environmental cues. A key input is amino acids, which act through the heterodimeric Rag GTPases (RagA or RagB bound to RagC or RagD) in order to promote the translocation of mTORC1 to the lysosomal surface, its site of activation. GATOR2 is a complex of unknown function that positively regulates mTORC1 signaling by acting upstream of or in parallel to GATOR1, which is a GTPase-activating protein (GAP) for RagA or RagB and an inhibitor of the amino-acid-sensing pathway. Here, we find that the Sestrins, a family of poorly understood growth regulators (Sestrin1–Sestrin3), interact with GATOR2 in an amino-acid-sensitive fashion. Sestrin2-mediated inhibition of mTORC1 signaling requires GATOR1 and the Rag GTPases, and the Sestrins regulate the localization of mTORC1 in response to amino acids. Thus, we identify the Sestrins as GATOR2-interacting proteins that regulate the amino-acid-sensing branch of the mTORC1 pathway. : The mTORC1 kinase is a major growth regulator that responds to numerous environmental inputs, including amino acids. Chantranupong et al. now identify the Sestrins as components of the mTORC1 amino-acid-sensing pathway. The Sestrins interact with GATOR2 in an amino-acid-sensitive manner and function as negative regulators of the pathway by preventing proper mTORC1 localization to the lysosome in response to amino acids.
