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

Nature
Authors
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.

Year of Publication
2017
Journal
Nature
Volume
543
Issue
7645
Pages
438-442
Date Published
2017 03 16
ISSN
1476-4687
DOI
10.1038/nature21423
PubMed ID
28199306
PubMed Central ID
PMC5360989
Links
Grant list
R01 CA103866 / CA / NCI NIH HHS / United States
R37 NS031348 / NS / NINDS NIH HHS / United States
F30 CA189333 / CA / NCI NIH HHS / United States
T32 GM007753 / GM / NIGMS NIH HHS / United States
F30 CA210373 / CA / NCI NIH HHS / United States
F31 CA180271 / CA / NCI NIH HHS / United States
R37 AI047389 / AI / NIAID NIH HHS / United States
HHMI / Howard Hughes Medical Institute / United States