WIPI3 and WIPI4 β-propellers are scaffolds for LKB1-AMPK-TSC signalling circuits in the control of autophagy

Daniela Bakula, Amelie J. Müller, Theresia Zuleger, Zsuzsanna Takacs, Mirita Franz-Wachtel, Ann-Katrin Thost, Daniel Brigger, Mario P. Tschan, Tancred Frickey, Horst Robenek, Boris Macek and Tassula Proikas-Cezanne ()
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Daniela Bakula: Interfaculty Institute of Cell Biology, Eberhard Karls University Tuebingen
Amelie J. Müller: Interfaculty Institute of Cell Biology, Eberhard Karls University Tuebingen
Theresia Zuleger: Interfaculty Institute of Cell Biology, Eberhard Karls University Tuebingen
Zsuzsanna Takacs: Interfaculty Institute of Cell Biology, Eberhard Karls University Tuebingen
Mirita Franz-Wachtel: Proteome Center Tuebingen, Interfaculty Institute of Cell Biology, Eberhard Karls University Tuebingen
Ann-Katrin Thost: Interfaculty Institute of Cell Biology, Eberhard Karls University Tuebingen
Daniel Brigger: Institute of Pathology, University of Bern
Mario P. Tschan: Institute of Pathology, University of Bern
Tancred Frickey: Applied Bioinformatics, Konstanz University
Horst Robenek: Institute of Experimental Musculoskeletal Medicine, University Hospital Muenster
Boris Macek: International Max Planck Research School 'From Molecules to Organisms', Max Planck Institute for Developmental Biology and Eberhard Karls University Tuebingen
Tassula Proikas-Cezanne: Interfaculty Institute of Cell Biology, Eberhard Karls University Tuebingen

Nature Communications, 2017, vol. 8, issue 1, 1-18

Abstract: Abstract Autophagy is controlled by AMPK and mTOR, both of which associate with ULK1 and control the production of phosphatidylinositol 3-phosphate (PtdIns3P), a prerequisite for autophagosome formation. Here we report that WIPI3 and WIPI4 scaffold the signal control of autophagy upstream of PtdIns3P production and have a role in the PtdIns3P effector function of WIPI1-WIPI2 at nascent autophagosomes. In response to LKB1-mediated AMPK stimulation, WIPI4-ATG2 is released from a WIPI4-ATG2/AMPK-ULK1 complex and translocates to nascent autophagosomes, controlling their size, to which WIPI3, in complex with FIP200, also contributes. Upstream, WIPI3 associates with AMPK-activated TSC complex at lysosomes, regulating mTOR. Our WIPI interactome analysis reveals the scaffold functions of WIPI proteins interconnecting autophagy signal control and autophagosome formation. Our functional kinase screen uncovers a novel regulatory link between LKB1-mediated AMPK stimulation that produces a direct signal via WIPI4, and we show that the AMPK-related kinases NUAK2 and BRSK2 regulate autophagy through WIPI4.

Date: 2017
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DOI: 10.1038/ncomms15637

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