The CASTOR Proteins Are Arginine Sensors for the mTORC1 Pathway

Cell. 2016 Mar 24;165(1):153-164. doi: 10.1016/j.cell.2016.02.035. Epub 2016 Mar 10.

Abstract

Amino acids signal to the mTOR complex I (mTORC1) growth pathway through the Rag GTPases. Multiple distinct complexes regulate the Rags, including GATOR1, a GTPase activating protein (GAP), and GATOR2, a positive regulator of unknown molecular function. Arginine stimulation of cells activates mTORC1, but how it is sensed is not well understood. Recently, SLC38A9 was identified as a putative lysosomal arginine sensor required for arginine to activate mTORC1 but how arginine deprivation represses mTORC1 is unknown. Here, we show that CASTOR1, a previously uncharacterized protein, interacts with GATOR2 and is required for arginine deprivation to inhibit mTORC1. CASTOR1 homodimerizes and can also heterodimerize with the related protein, CASTOR2. Arginine disrupts the CASTOR1-GATOR2 complex by binding to CASTOR1 with a dissociation constant of ~30 μM, and its arginine-binding capacity is required for arginine to activate mTORC1 in cells. Collectively, these results establish CASTOR1 as an arginine sensor for the mTORC1 pathway.

Publication types

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

MeSH terms

  • Arginine / metabolism*
  • Carrier Proteins / metabolism*
  • HEK293 Cells
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Mechanistic Target of Rapamycin Complex 1
  • Multiprotein Complexes / metabolism
  • Protein Multimerization
  • TOR Serine-Threonine Kinases / metabolism

Substances

  • CASTOR1 protein, human
  • CASTOR2 protein, human
  • Carrier Proteins
  • Intracellular Signaling Peptides and Proteins
  • Multiprotein Complexes
  • Arginine
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1