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Nature. 2017 Mar 16;543(7645):438-442. doi: 10.1038/nature21423. Epub 2017 Feb 15.

KICSTOR recruits GATOR1 to the lysosome and is necessary for nutrients to regulate mTORC1.

Wolfson RL1,2,3,4, Chantranupong L1,2,3,4, Wyant GA1,2,3,4, Gu X1,2,3,4, Orozco JM1,2,3,4, Shen K1,2,3,4, Condon KJ1,2,3,4, Petri S5, Kedir J1,2,3,4, Scaria SM1,2,3,4, Abu-Remaileh M1,2,3,4, Frankel WN5, Sabatini DM1,2,3,4.

Author information

1
Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology, Department of Biology, 9 Cambridge Center, Cambridge, Massachusetts 02142, USA.
2
Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
3
Koch Institute for Integrative Cancer Research, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA.
4
Broad Institute of Harvard and Massachusetts Institute of Technology, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA.
5
Department of Genetics and Development and Institute for Genomic Medicine, Columbia University Medical Center, New York, New York 10032, USA.

Abstract

The mechanistic target of rapamycin complex 1 (mTORC1) is a central regulator of cell growth that responds to diverse environmental signals and is deregulated in many human diseases, including cancer and epilepsy. Amino acids are a key input to this system, and act through the Rag GTPases to promote the translocation of mTORC1 to the lysosomal surface, its site of activation. Multiple protein complexes regulate the Rag GTPases in response to amino acids, including GATOR1, a GTPase activating protein for RAGA, and GATOR2, a positive regulator of unknown molecular function. Here we identify a protein complex (KICSTOR) that is composed of four proteins, KPTN, ITFG2, C12orf66 and SZT2, and that is required for amino acid or glucose deprivation to inhibit mTORC1 in cultured human cells. In mice that lack SZT2, mTORC1 signalling is increased in several tissues, including in neurons in the brain. KICSTOR localizes to lysosomes; binds and recruits GATOR1, but not GATOR2, to the lysosomal surface; and is necessary for the interaction of GATOR1 with its substrates, the Rag GTPases, and with GATOR2. Notably, several KICSTOR components are mutated in neurological diseases associated with mutations that lead to hyperactive mTORC1 signalling. Thus, KICSTOR is a lysosome-associated negative regulator of mTORC1 signalling, which, like GATOR1, is mutated in human disease.

PMID:
28199306
PMCID:
PMC5360989
DOI:
10.1038/nature21423
[Indexed for MEDLINE]
Free PMC Article

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