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.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / chemistry
  • Adaptor Proteins, Signal Transducing / metabolism
  • Autophagy*
  • Autophagy-Related Protein-1 Homolog / chemistry
  • Autophagy-Related Proteins / chemistry
  • Carrier Proteins / chemistry*
  • Cell Line, Tumor
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Intracellular Signaling Peptides and Proteins / chemistry
  • Lysosomes / metabolism
  • Phagosomes / metabolism
  • Phosphatidylinositol Phosphates / chemistry
  • Protein Binding
  • Protein Conformation
  • Protein-Serine-Threonine Kinases / chemistry*
  • Signal Transduction*
  • Vesicular Transport Proteins / chemistry

Substances

  • ATG2B protein, human
  • Adaptor Proteins, Signal Transducing
  • Autophagy-Related Proteins
  • Carrier Proteins
  • Intracellular Signaling Peptides and Proteins
  • Phosphatidylinositol Phosphates
  • Vesicular Transport Proteins
  • WDR45 protein, human
  • WDR45B protein, human
  • phosphatidylinositol 3-phosphate
  • STK11 protein, human
  • Autophagy-Related Protein-1 Homolog
  • PRKAA1 protein, human
  • Protein-Serine-Threonine Kinases
  • ULK1 protein, human
  • AMP-Activated Protein Kinases