TORC1 Determines Fab1 Lipid Kinase Function at Signaling Endosomes and Vacuoles

Curr Biol. 2021 Jan 25;31(2):297-309.e8. doi: 10.1016/j.cub.2020.10.026. Epub 2020 Nov 5.

Abstract

Organelles of the endomembrane system maintain their identity and integrity during growth or stress conditions by homeostatic mechanisms that regulate membrane flux and biogenesis. At lysosomes and endosomes, the Fab1 lipid kinase complex and the nutrient-regulated target of rapamycin complex 1 (TORC1) control the integrity of the endolysosomal homeostasis and cellular metabolism. Both complexes are functionally connected as Fab1-dependent generation of PI(3,5)P2 supports TORC1 activity. Here, we identify Fab1 as a target of TORC1 on signaling endosomes, which are distinct from multivesicular bodies, and provide mechanistic insight into their crosstalk. Accordingly, TORC1 can phosphorylate Fab1 proximal to its PI3P-interacting FYVE domain, which causes Fab1 to shift to signaling endosomes, where it generates PI(3,5)P2. This, in turn, regulates (1) vacuole morphology, (2) recruitment of TORC1 and the TORC1-regulatory Rag GTPase-containing EGO complex to signaling endosomes, and (3) TORC1 activity. Thus, our study unravels a regulatory feedback loop between TORC1 and the Fab1 complex that controls signaling at endolysosomes.

Keywords: Fab1; PI(3,5)P2; TORC1; cellular signaling; late endosome; lipid kinase; lysosome; phosphoinositide; signaling endosome; vacuole.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Endosomes / metabolism*
  • Enzyme Assays
  • Feedback, Physiological
  • Mechanistic Target of Rapamycin Complex 1 / metabolism*
  • Phosphorylation / physiology
  • Phosphotransferases (Alcohol Group Acceptor) / genetics
  • Phosphotransferases (Alcohol Group Acceptor) / isolation & purification
  • Phosphotransferases (Alcohol Group Acceptor) / metabolism*
  • Recombinant Proteins / genetics
  • Recombinant Proteins / isolation & purification
  • Recombinant Proteins / metabolism
  • Saccharomyces cerevisiae
  • Saccharomyces cerevisiae Proteins / genetics
  • Saccharomyces cerevisiae Proteins / isolation & purification
  • Saccharomyces cerevisiae Proteins / metabolism*
  • Signal Transduction
  • Vacuoles / metabolism*

Substances

  • Recombinant Proteins
  • Saccharomyces cerevisiae Proteins
  • FAB1 protein, S cerevisiae
  • Phosphotransferases (Alcohol Group Acceptor)
  • Mechanistic Target of Rapamycin Complex 1