Differential regulation of distinct Vps34 complexes by AMPK in nutrient stress and autophagy

Cell. 2013 Jan 17;152(1-2):290-303. doi: 10.1016/j.cell.2012.12.016.

Abstract

Autophagy is a stress response protecting cells from unfavorable conditions, such as nutrient starvation. The class III phosphatidylinositol-3 kinase, Vps34, forms multiple complexes and regulates both intracellular vesicle trafficking and autophagy induction. Here, we show that AMPK plays a key role in regulating different Vps34 complexes. AMPK inhibits the nonautophagy Vps34 complex by phosphorylating T163/S165 in Vps34 and therefore suppresses overall PI(3)P production and protects cells from starvation. In parallel, AMPK activates the proautophagy Vps34 complex by phosphorylating S91/S94 in Beclin1 to induce autophagy. Atg14L, an autophagy-essential gene present only in the proautophagy Vps34 complex, inhibits Vps34 phosphorylation but increases Beclin1 phosphorylation by AMPK. As such, Atg14L dictates the differential regulation (either inhibition or activation) of different Vps34 complexes in response to glucose starvation. Our study reveals an intricate molecular regulation of Vps34 complexes by AMPK in nutrient stress response and autophagy.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Apoptosis Regulatory Proteins / chemistry
  • Apoptosis Regulatory Proteins / metabolism
  • Autophagy*
  • Autophagy-Related Proteins
  • Beclin-1
  • Class III Phosphatidylinositol 3-Kinases / genetics
  • Class III Phosphatidylinositol 3-Kinases / metabolism*
  • Glucose / metabolism
  • Mice
  • Molecular Sequence Data
  • Multiprotein Complexes / metabolism
  • Phosphorylation
  • Protein Kinases / chemistry
  • Protein Kinases / genetics
  • Protein Kinases / metabolism*
  • Sequence Alignment
  • Vesicular Transport Proteins / metabolism

Substances

  • Apoptosis Regulatory Proteins
  • Atg14 protein, mouse
  • Autophagy-Related Proteins
  • Beclin-1
  • Becn1 protein, mouse
  • Multiprotein Complexes
  • Vesicular Transport Proteins
  • Protein Kinases
  • AMP-activated protein kinase kinase
  • Class III Phosphatidylinositol 3-Kinases
  • Glucose