TORC1 Determines Fab1 Lipid Kinase Function at Signaling Endosomes and Vacuoles.

Current biology : CB 2021 Jan 25

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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. Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.

Citation

Zilei Chen, Pedro Carpio Malia, Riko Hatakeyama, Raffaele Nicastro, Zehan Hu, Marie-Pierre Péli-Gulli, Jieqiong Gao, Taki Nishimura, Elja Eskes, Christopher J Stefan, Joris Winderickx, Jörn Dengjel, Claudio De Virgilio, Christian Ungermann. TORC1 Determines Fab1 Lipid Kinase Function at Signaling Endosomes and Vacuoles. Current biology : CB. 2021 Jan 25;31(2):297-309.e8