TORC1 determines Fab1 lipid kinase function at signaling endosomes and vacuoles

Zilei Chen, Pedro Carpio Malia, Riko Hatakeyama, Raffaele Nicastro, Zehan Hu, MariePierre Péli-Gulli, Jieqiong Gao, Taki Nishimura, Elja Eskes, Christopher J. Stefan, Joris Winderickx, Joern Dengje, Claudio De Virgilio* (Corresponding Author), Christian Ungermann* (Corresponding Author)

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

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 endo-lysosomal 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 (i) vacuole morphology, (ii) recruitment of TORC1 and the TORC1-regulatory Rag GTPase-containing EGO complex to signaling endosomes, and (iii) TORC1 activity. Thus, our study unravels a regulatory feedback loop between TORC1 and the Fab1 complex that controls
signaling at endolysosomes.
Original languageEnglish
Pages (from-to)297-309
Number of pages12
JournalCurrent Biology
Volume31
Issue number2
Early online date5 Nov 2020
DOIs
Publication statusPublished - 25 Jan 2021

Keywords

  • Fab1
  • TORC1
  • lysosome
  • vacuole
  • phosphoinositide
  • signaling endosome
  • PI(3,5)P2
  • lipid kinase
  • cellular signaling
  • late endosome

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