Target of rapamycin (TOR) is a serine/threonine kinase, and plays fundamental roles in regulating cell growth and metabolism by coordinating diverse cellular processes including transcription, translation and autophagy. These findings suggest that Lam2 and Npr2-Npr3 function together as a tether for GDP-bound Gtr1 to the vacuolar membrane, thereby suppressing TORC1 activity for multiple cellular functions. Furthermore, Lam2 physically interacted with Npr2 and Gtr1. Consistently, overexpression of GDP-locked Gtr1 S20L or GTP-locked Gtr2 Q60L, which suppress TORC1 activity in budding yeast, rescued the growth defect of Δ gtr1 cells or Δ gtr2 cells, respectively, and the loss of Lam2, Npr2 or Npr3 similarly diminished the vacuolar localization and the protein levels of Gtr1 and Gtr2. These phenotypes were rescued by TORC1 inhibition using pharmacological or genetic means, and the loss of Lam2, Gtr1, Gtr2, Npr2 or Npr3 disinhibited TORC1 activity under nitrogen depletion, as measured by Rps6 phosphorylation. Using fission yeast as a model organism, here we found that the loss of Lam2 (SPBC1778.05c), a homolog of a Ragulator component LAMTOR2, as well as the loss of Gtr1 or Gtr2 phenocopies the loss of Npr2 or Npr3, homologs of GATOR components Nprl2 or Nprl3, respectively. However, the functions of components in these complexes remain elusive.
It is thought that the Ragulator complex and the GATOR (GAP activity towards Rags) complex regulate RagA/B as its GDP/GTP exchange factor (GEF) and GTPase-activating protein (GAP), respectively. In mammalian cells, mTORC1 activity is regulated by Rag GTPases.