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Journal Article

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

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Bakula,  D
IMPRS From Molecules to Organisms, Max Planck Institute for Developmental Biology, Max Planck Society;

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Müller,  AJ
IMPRS From Molecules to Organisms, Max Planck Institute for Developmental Biology, Max Planck Society;

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Takacs,  Z
IMPRS From Molecules to Organisms, Max Planck Institute for Developmental Biology, Max Planck Society;

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Macek,  B
IMPRS From Molecules to Organisms, Max Planck Institute for Developmental Biology, Max Planck Society;

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Proikas-Cezanne,  T
IMPRS From Molecules to Organisms, Max Planck Institute for Developmental Biology, Max Planck Society;

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Citation

Bakula, D., Müller, A., Zuleger, T., Takacs, Z., Franz-Wachtel, M., Thost, A.-K., et al. (2017). WIPI3 and WIPI4 β-propellers are scaffolds for LKB1-AMPK-TSC signalling circuits in the control of autophagy. Nature Communications, 8: 15637. doi:10.1038/ncomms15637.


Cite as: https://hdl.handle.net/21.11116/0000-000A-8CFD-C
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.