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

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  • Daniela Bakula

    (Interfaculty Institute of Cell Biology, Eberhard Karls University Tuebingen
    International Max Planck Research School 'From Molecules to Organisms', Max Planck Institute for Developmental Biology and Eberhard Karls University Tuebingen)

  • Amelie J. Müller

    (Interfaculty Institute of Cell Biology, Eberhard Karls University Tuebingen
    International Max Planck Research School 'From Molecules to Organisms', Max Planck Institute for Developmental Biology and 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
    International Max Planck Research School 'From Molecules to Organisms', Max Planck Institute for Developmental Biology and 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
    Proteome Center Tuebingen, Interfaculty Institute of Cell Biology, Eberhard Karls University Tuebingen)

  • Tassula Proikas-Cezanne

    (Interfaculty Institute of Cell Biology, Eberhard Karls University Tuebingen
    International Max Planck Research School 'From Molecules to Organisms', Max Planck Institute for Developmental Biology and Eberhard Karls University Tuebingen)

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.

Suggested Citation

  • 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 & T, 2017. "WIPI3 and WIPI4 β-propellers are scaffolds for LKB1-AMPK-TSC signalling circuits in the control of autophagy," Nature Communications, Nature, vol. 8(1), pages 1-18, August.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms15637
    DOI: 10.1038/ncomms15637
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    Cited by:

    1. Simonetta M. Leto & Elena Grassi & Marco Avolio & Valentina Vurchio & Francesca Cottino & Martina Ferri & Eugenia R. Zanella & Sofia Borgato & Giorgio Corti & Laura Blasio & Desiana Somale & Marianela, 2024. "XENTURION is a population-level multidimensional resource of xenografts and tumoroids from metastatic colorectal cancer patients," Nature Communications, Nature, vol. 15(1), pages 1-22, December.

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