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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amino Acids / metabolism
  • Animals
  • Carrier Proteins / chemistry
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Cell Line
  • Female
  • GTPase-Activating Proteins
  • Glucose / deficiency
  • Glucose / metabolism
  • Humans
  • Integrin alpha Chains
  • Lysosomes / metabolism*
  • Male
  • Mechanistic Target of Rapamycin Complex 1
  • Mice
  • Microfilament Proteins / chemistry
  • Microfilament Proteins / genetics
  • Microfilament Proteins / metabolism
  • Monomeric GTP-Binding Proteins / metabolism
  • Multiprotein Complexes / antagonists & inhibitors
  • Multiprotein Complexes / chemistry
  • Multiprotein Complexes / genetics
  • Multiprotein Complexes / metabolism*
  • Mutation
  • Nerve Tissue Proteins / chemistry
  • Nerve Tissue Proteins / deficiency
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Neurons / metabolism
  • Protein Binding
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism
  • Signal Transduction
  • Substrate Specificity
  • TOR Serine-Threonine Kinases / antagonists & inhibitors
  • TOR Serine-Threonine Kinases / metabolism*

Substances

  • Amino Acids
  • C12orf66 protein, human
  • Carrier Proteins
  • DEPDC5 protein, human
  • GTPase-Activating Proteins
  • ITFG2 protein, human
  • Integrin alpha Chains
  • KPTN protein, human
  • Microfilament Proteins
  • Multiprotein Complexes
  • Nerve Tissue Proteins
  • Repressor Proteins
  • SZT2 protein, human
  • Szt2 protein, mouse
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1
  • Monomeric GTP-Binding Proteins
  • Glucose