KICSTOR recruits GATOR1 to the lysosome and is necessary for nutrients to regulate mTORC1
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Author(s)
Shen, Kuang
Petri, Sabrina
Abu-Remaileh, Monther
Frankel, Wayne N.
Wolfson, Rachel Laura
Chantranupong, Lynne
Wyant, Gregory Andrew
Gu, Xin
Orozco Segrera, Jose
Condon, Kendall Janine
Date Issued
February 2017
Journal
Nature
Publisher
Nature Publishing Group
Citation
Wolfson, Rachel L. et al. “KICSTOR Recruits GATOR1 to the Lysosome and Is Necessary for Nutrients to Regulate mTORC1.” Nature 543, 7645 (February 2017): 438–442 © 2017 Macmillan Publishers Limited, part of Springer Nature
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Author's final manuscript
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.
MIT Department
Massachusetts Institute of Technology. Department of Biology
Koch Institute for Integrative Cancer Research at MIT
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DOI of Published Version
https://doi.org/10.1038/NATURE21423
