KICSTOR recruits GATOR1 to the lysosome and is necessary for nutrients to regulate mTORC1
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...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
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Nature Publishing Group
2018
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| Online Access: | http://hdl.handle.net/1721.1/116769 https://orcid.org/0000-0002-9535-7664 https://orcid.org/0000-0001-9388-1633 https://orcid.org/0000-0003-4642-3706 https://orcid.org/0000-0002-3393-6927 https://orcid.org/0000-0002-4364-5912 https://orcid.org/0000-0002-9515-8892 https://orcid.org/0000-0002-1565-9049 https://orcid.org/0000-0002-1446-7256 |
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| author | 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 Kedir, Jibril Fetu Scaria, Sonia M. Sabatini, David |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology 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 Kedir, Jibril Fetu Scaria, Sonia M. Sabatini, David |
| author_sort | Shen, Kuang |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T13:23:48Z |
| format | Article |
| id | mit-1721.1/116769 |
| institution | Massachusetts Institute of Technology |
| last_indexed | 2024-09-23T13:23:48Z |
| publishDate | 2018 |
| publisher | Nature Publishing Group |
| record_format | dspace |
| spelling | mit-1721.1/1167692022-09-28T13:54:42Z KICSTOR recruits GATOR1 to the lysosome and is necessary for nutrients to regulate mTORC1 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 Kedir, Jibril Fetu Scaria, Sonia M. Sabatini, David Massachusetts Institute of Technology. Department of Biology Koch Institute for Integrative Cancer Research at MIT Wolfson, Rachel Laura Chantranupong, Lynne Wyant, Gregory Andrew Gu, Xin Orozco Segrera, Jose Condon, Kendall Janine Kedir, Jibril Fetu Scaria, Sonia M. Sabatini, David 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. National Institutes of Health (U.S.) (Grant R01CA103866) National Institutes of Health (U.S.) (Grant R37AI47389) United States. Department of Defense (Award W81XWH-07-0448) National Institutes of Health (U.S.) (Grant T32GM007753) National Institutes of Health (U.S.) (Grant F30CA189333) National Institutes of Health (U.S.) (Grant F31 CA180271) National Institutes of Health (U.S.) (Grant T32GM007753) National Institutes of Health (U.S.) (Grant F30CA210373) National Science Foundation (U.S.) (Grant 2016197106) 2018-07-03T18:34:16Z 2018-07-03T18:34:16Z 2017-02 2016-11 2018-07-03T18:01:18Z Article http://purl.org/eprint/type/JournalArticle 0028-0836 1476-4687 http://hdl.handle.net/1721.1/116769 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 https://orcid.org/0000-0002-9535-7664 https://orcid.org/0000-0001-9388-1633 https://orcid.org/0000-0003-4642-3706 https://orcid.org/0000-0002-3393-6927 https://orcid.org/0000-0002-4364-5912 https://orcid.org/0000-0002-9515-8892 https://orcid.org/0000-0002-1565-9049 https://orcid.org/0000-0002-1446-7256 http://dx.doi.org/10.1038/NATURE21423 Nature Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf Nature Publishing Group PMC |
| spellingShingle | 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 Kedir, Jibril Fetu Scaria, Sonia M. Sabatini, David KICSTOR recruits GATOR1 to the lysosome and is necessary for nutrients to regulate mTORC1 |
| title | KICSTOR recruits GATOR1 to the lysosome and is necessary for nutrients to regulate mTORC1 |
| title_full | KICSTOR recruits GATOR1 to the lysosome and is necessary for nutrients to regulate mTORC1 |
| title_fullStr | KICSTOR recruits GATOR1 to the lysosome and is necessary for nutrients to regulate mTORC1 |
| title_full_unstemmed | KICSTOR recruits GATOR1 to the lysosome and is necessary for nutrients to regulate mTORC1 |
| title_short | KICSTOR recruits GATOR1 to the lysosome and is necessary for nutrients to regulate mTORC1 |
| title_sort | kicstor recruits gator1 to the lysosome and is necessary for nutrients to regulate mtorc1 |
| url | http://hdl.handle.net/1721.1/116769 https://orcid.org/0000-0002-9535-7664 https://orcid.org/0000-0001-9388-1633 https://orcid.org/0000-0003-4642-3706 https://orcid.org/0000-0002-3393-6927 https://orcid.org/0000-0002-4364-5912 https://orcid.org/0000-0002-9515-8892 https://orcid.org/0000-0002-1565-9049 https://orcid.org/0000-0002-1446-7256 |
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