Journal
NATURE COMMUNICATIONS
Volume 8, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ncomms15637
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Funding
- German Research Foundation (DFG) [SFB 773, GRK 1302]
- Swiss National Science Foundation [31003A_143739]
- Forschungsschwerpunktprogramm Baden-Wuerttemberg [Kapitel 1403, Tit. Gr. 74]
- Landesgraduiertenforderung (LGFG) Baden-Wuerttemberg
- International Max Planck Research School 'From Molecules to Organisms', Tuebingen, Germany
- Swiss National Science Foundation (SNF) [31003A_143739] Funding Source: Swiss National Science Foundation (SNF)
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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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