ULK1 induces autophagy by phosphorylating Beclin-1 and activating VPS34 lipid kinase

Nat Cell Biol. 2013 Jul;15(7):741-50. doi: 10.1038/ncb2757. Epub 2013 May 19.

Abstract

Autophagy is the primary cellular catabolic program activated in response to nutrient starvation. Initiation of autophagy, particularly by amino-acid withdrawal, requires the ULK kinases. Despite its pivotal role in autophagy initiation, little is known about the mechanisms by which ULK promotes autophagy. Here we describe a molecular mechanism linking ULK to the pro-autophagic lipid kinase VPS34. Following amino-acid starvation or mTOR inhibition, the activated ULK1 phosphorylates Beclin-1 on Ser 14, thereby enhancing the activity of the ATG14L-containing VPS34 complexes. The Beclin-1 Ser 14 phosphorylation by ULK is required for full autophagic induction in mammals and this requirement is conserved in Caenorhabditis elegans. Our study reveals a molecular link from ULK1 to activation of the autophagy-specific VPS34 complex and autophagy induction.

Publication types

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

MeSH terms

  • Amino Acids / deficiency
  • Animals
  • Apoptosis Regulatory Proteins / metabolism*
  • Autophagy*
  • Autophagy-Related Protein-1 Homolog
  • Autophagy-Related Proteins
  • Beclin-1
  • Caenorhabditis elegans
  • Cells, Cultured
  • Class III Phosphatidylinositol 3-Kinases / metabolism*
  • Embryo, Mammalian / cytology
  • Embryo, Mammalian / metabolism*
  • Enzyme Activation
  • Fibroblasts / cytology
  • Fibroblasts / metabolism*
  • Humans
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Kidney / cytology
  • Kidney / metabolism
  • Mice
  • Mice, Knockout
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / physiology*
  • Serine / metabolism
  • Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
  • Starvation
  • TOR Serine-Threonine Kinases / metabolism
  • Tumor Suppressor Proteins / metabolism
  • Vesicular Transport Proteins / metabolism

Substances

  • Amino Acids
  • Apoptosis Regulatory Proteins
  • Atg14 protein, mouse
  • Autophagy-Related Proteins
  • Beclin-1
  • Becn1 protein, mouse
  • Intracellular Signaling Peptides and Proteins
  • Rb1cc1 protein, mouse
  • Tumor Suppressor Proteins
  • UVRAG protein, mouse
  • Vesicular Transport Proteins
  • Serine
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse
  • Class III Phosphatidylinositol 3-Kinases
  • Autophagy-Related Protein-1 Homolog
  • Protein-Serine-Threonine Kinases
  • Ulk1 protein, mouse