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; Christian  Ungermann

doi:10.1016/j.cub.2020.10.026

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 journal › Article › peer-review

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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 language	English
Pages (from-to)	297-309
Number of pages	12
Journal	Current Biology
Volume	31
Issue number	2
Early online date	5 Nov 2020
DOIs	https://doi.org/10.1016/j.cub.2020.10.026
Publication status	Published - 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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@article{0decbd32796441c6ae63fa4ff105d810,

title = "TORC1 determines Fab1 lipid kinase function at signaling endosomes and vacuoles",

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 ofrapamycin 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 signalingendosomes, 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 controlssignaling at endolysosomes.",

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

author = "Zilei Chen and {Carpio Malia}, Pedro and Riko Hatakeyama and Raffaele Nicastro and Zehan Hu and MariePierre P{\'e}li-Gulli and Jieqiong Gao and Taki Nishimura and Elja Eskes and Stefan, {Christopher J.} and Joris Winderickx and Joern Dengje and {De Virgilio}, Claudio and Christian Ungermann",

note = "Acknowledgments: We thank Lars Langemeyer for feedback, all members from the Ungermann lab for discussions, and Kathrin Auffarth, Angela Perz, and Malika Jaquenoud for expert technical assistance. This work was supported by the DFG (UN111/10-1 to C.U.), the Canton of Fribourg (to J.D. and C.D.V.), and the Swiss National Science Foundation (310030_166474/184671 to C.D.V. and 310030_184781 and 316030_177088 to J.D.). Z.C. received support from a travel stipend of the Boehringer Ingelheim Fonds. P.C.M. received additional support from the graduate program of the Collaborative Research Center 944 (SFB 944) and Department of Biology/Chemistry Osnabr{\"u}ck. E.E. received a fellowship of FWO Vlaanderen, Belgium (SB-FWO 1S06419N). Author Contributions: Z.C. and P.C.M. conducted all experiments on Fab1 localization and function; R.H. conducted experiments on development and analysis of the Sch91–183 probe; R.N., Z.H., M.-P.P.-G., and J.D. did the phosphorylation assays and analyses; and E.E. and J.W. conceived and performed the initial Sch9 mapping. T.N. and C.J.S. did the lipid analysis of the mutant alleles. J.G. analyzed microcopy data with Z.C. C.D.V. and C.U. conceived the study and wrote the manuscript with support of J.W.",

year = "2021",

month = jan,

day = "25",

doi = "10.1016/j.cub.2020.10.026",

language = "English",

volume = "31",

pages = "297--309",

journal = "Current Biology",

issn = "0960-9822",

publisher = "Cell Press",

number = "2",

}

TY - JOUR

T1 - TORC1 determines Fab1 lipid kinase function at signaling endosomes and vacuoles

AU - Chen, Zilei

AU - Carpio Malia, Pedro

AU - Hatakeyama, Riko

AU - Nicastro, Raffaele

AU - Hu, Zehan

AU - Péli-Gulli, MariePierre

AU - Gao, Jieqiong

AU - Nishimura, Taki

AU - Eskes, Elja

AU - Stefan, Christopher J.

AU - Winderickx, Joris

AU - Dengje, Joern

AU - De Virgilio, Claudio

AU - Ungermann, Christian

N1 - Acknowledgments: We thank Lars Langemeyer for feedback, all members from the Ungermann lab for discussions, and Kathrin Auffarth, Angela Perz, and Malika Jaquenoud for expert technical assistance. This work was supported by the DFG (UN111/10-1 to C.U.), the Canton of Fribourg (to J.D. and C.D.V.), and the Swiss National Science Foundation (310030_166474/184671 to C.D.V. and 310030_184781 and 316030_177088 to J.D.). Z.C. received support from a travel stipend of the Boehringer Ingelheim Fonds. P.C.M. received additional support from the graduate program of the Collaborative Research Center 944 (SFB 944) and Department of Biology/Chemistry Osnabrück. E.E. received a fellowship of FWO Vlaanderen, Belgium (SB-FWO 1S06419N). Author Contributions: Z.C. and P.C.M. conducted all experiments on Fab1 localization and function; R.H. conducted experiments on development and analysis of the Sch91–183 probe; R.N., Z.H., M.-P.P.-G., and J.D. did the phosphorylation assays and analyses; and E.E. and J.W. conceived and performed the initial Sch9 mapping. T.N. and C.J.S. did the lipid analysis of the mutant alleles. J.G. analyzed microcopy data with Z.C. C.D.V. and C.U. conceived the study and wrote the manuscript with support of J.W.

PY - 2021/1/25

Y1 - 2021/1/25

N2 - 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 ofrapamycin 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 signalingendosomes, 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 controlssignaling at endolysosomes.

AB - 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 ofrapamycin 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 signalingendosomes, 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 controlssignaling at endolysosomes.

KW - Fab1

KW - TORC1

KW - lysosome

KW - vacuole

KW - phosphoinositide

KW - signaling endosome

KW - PI(3,5)P2

KW - lipid kinase

KW - cellular signaling

KW - late endosome

UR - http://www.scopus.com/inward/record.url?scp=85096927307&partnerID=8YFLogxK

U2 - 10.1016/j.cub.2020.10.026

DO - 10.1016/j.cub.2020.10.026

M3 - Article

VL - 31

SP - 297

EP - 309

JO - Current Biology

JF - Current Biology

SN - 0960-9822

IS - 2

ER -

TORC1 determines Fab1 lipid kinase function at signaling endosomes and vacuoles

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TORC1 determines Fab1 lipid kinase function at signaling endosomes and vacuoles

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