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

  • Nat Commun. 2017 May 31;8:15637. doi: 10.1038/ncomms15637.
Daniela Bakula  1  2 ,  Amelie J Müller  1  2 ,  Theresia Zuleger  1 ,  Zsuzsanna Takacs  1  2 ,  Mirita Franz-Wachtel  3 ,  Ann-Katrin Thost  1 ,  Daniel Brigger  4 ,  Mario P Tschan  4 ,  Tancred Frickey  5 ,  Horst Robenek  6 ,  Boris Macek  2  3 ,  Tassula Proikas-Cezanne  1  2
Affiliations
  • 1. Department of Molecular Biology, Interfaculty Institute of Cell Biology, Eberhard Karls University Tuebingen, D-72076 Tuebingen, Germany.
  • 2. International Max Planck Research School 'From Molecules to Organisms', Max Planck Institute for Developmental Biology and Eberhard Karls University Tuebingen, D-72076 Tuebingen, Germany.
  • 3. Proteome Center Tuebingen, Interfaculty Institute of Cell Biology, Eberhard Karls University Tuebingen, D-72076 Tuebingen, Germany.
  • 4. Division of Experimental Pathology, Institute of Pathology, University of Bern, CH-3008 Bern, Switzerland.
  • 5. Department of Biology, Applied Bioinformatics, Konstanz University, D-78457 Konstanz, Germany.
  • 6. Institute of Experimental Musculoskeletal Medicine, University Hospital Muenster, D-48149 Muenster, Germany.
PMID: 28561066 DOI: 10.1038/ncomms15637
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.