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Nat Commun. 2017 May 31;8:15637. doi: 10.1038/ncomms15637.

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

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Department of Molecular Biology, Interfaculty Institute of Cell Biology, Eberhard Karls University Tuebingen, D-72076 Tuebingen, Germany.
International Max Planck Research School 'From Molecules to Organisms', Max Planck Institute for Developmental Biology and Eberhard Karls University Tuebingen, D-72076 Tuebingen, Germany.
Proteome Center Tuebingen, Interfaculty Institute of Cell Biology, Eberhard Karls University Tuebingen, D-72076 Tuebingen, Germany.
Division of Experimental Pathology, Institute of Pathology, University of Bern, CH-3008 Bern, Switzerland.
Department of Biology, Applied Bioinformatics, Konstanz University, D-78457 Konstanz, Germany.
Institute of Experimental Musculoskeletal Medicine, University Hospital Muenster, D-48149 Muenster, Germany.


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.

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