Details

Autor(en) / Beteiligte

• Wolfson, Rachel L.
• Chantranupong, Lynne
• Wyant, Gregory A.
• Gu, Xin
• Orozco, Jose M.
• Shen, Kuang
• Condon, Kendall J.
• Petri, Sabrina
• Kedir, Jibril
• Scaria, Sonia M.
• Abu-Remaileh, Monther
• Frankel, Wayne N.
• Sabatini, David M.

Titel

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

Ist Teil von

• Nature (London), 2017-03, Vol.543 (7645), p.438-442

Ort / Verlag

London: Nature Publishing Group UK

Erscheinungsjahr

2017

Quelle

MEDLINE

Beschreibungen/Notizen

• A protein complex composed of KPTN, ITFG2, C12orf66 and SZT2, named KICSTOR, is necessary for lysosomal localization of GATOR1, interaction of GATOR1 with the Rag GTPases and GATOR2, and nutrient-dependent mTORC1 modulation. KICSTOR is a negative regulator of mTORC1 signalling The mechanistic target of rapamycin complex 1 (mTORC1) is a central regulator of cell growth and organismal homeostasis and is deregulated in many human diseases, including epilepsy and cancer. In response to nutrients, mTORC1 is recruited to the lysosome by the Rag family of GTPases, whose activity is regulated by the GATOR complex. Here David Sabatini and colleagues identify a four-membered protein complex that they term KICSTOR. It localizes to lysosomes and interacts with GATOR to negatively regulate the pathway through which mTORC1 senses nutrients. In mice lacking one of the KICSTOR subunits, SZT2, mTORC1 signalling is hyperactivated in several tissues. A related paper in this week's issue of Nature from Ming Li and colleagues identifies the protein SZT2 as a negative regulator of mTORC1 signalling. Together, the two papers offer insight into mTORC1 regulation at the lysosome and could have implications for diseases associated with hyperactive mTORC1 signalling. 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 1 , 2 , 3 . 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 4 . 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 5 , 6 , 7 , 8 , 9 , 10 . Thus, KICSTOR is a lysosome-associated negative regulator of mTORC1 signalling, which, like GATOR1, is mutated in human disease 11 , 12 .