ATG12 conjugation to ATG3 regulates mitochondrial homeostasis and cell death

Cell. 2010 Aug 20;142(4):590-600. doi: 10.1016/j.cell.2010.07.018.

Abstract

ATG12, an ubiquitin-like modifier required for macroautophagy, has a single known conjugation target, another autophagy regulator called ATG5. Here, we identify ATG3 as a substrate for ATG12 conjugation. ATG3 is the E2-like enzyme necessary for ATG8/LC3 lipidation during autophagy. ATG12-ATG3 complex formation requires ATG7 as the E1 enzyme and ATG3 autocatalytic activity as the E2, resulting in the covalent linkage of ATG12 onto a single lysine on ATG3. Surprisingly, disrupting ATG12 conjugation to ATG3 does not affect starvation-induced autophagy. Rather, the lack of ATG12-ATG3 complex formation produces an expansion in mitochondrial mass and inhibits cell death mediated by mitochondrial pathways. Overall, these results unveil a role for ATG12-ATG3 in mitochondrial homeostasis and implicate the ATG12 conjugation system in cellular functions distinct from the early steps of autophagosome formation.

Publication types

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

MeSH terms

  • Amino Acid Sequence
  • Autophagy
  • Autophagy-Related Protein 12
  • Autophagy-Related Protein 5
  • Autophagy-Related Protein 7
  • Autophagy-Related Proteins
  • Cell Death*
  • Cell Line
  • Cell Line, Tumor
  • Embryo, Mammalian / cytology
  • Fibroblasts / metabolism
  • HeLa Cells
  • Humans
  • Microtubule-Associated Proteins / metabolism
  • Mitochondria / metabolism*
  • Molecular Sequence Data
  • Phagosomes / metabolism
  • Proteins / chemistry
  • Proteins / metabolism
  • Small Ubiquitin-Related Modifier Proteins / chemistry
  • Small Ubiquitin-Related Modifier Proteins / metabolism*
  • Ubiquitin-Conjugating Enzymes / chemistry
  • Ubiquitin-Conjugating Enzymes / metabolism*

Substances

  • ATG12 protein, human
  • ATG5 protein, human
  • Atg12 protein, mouse
  • Atg7 protein, mouse
  • Autophagy-Related Protein 12
  • Autophagy-Related Protein 5
  • Autophagy-Related Proteins
  • Microtubule-Associated Proteins
  • Proteins
  • Small Ubiquitin-Related Modifier Proteins
  • Ubiquitin-Conjugating Enzymes
  • Autophagy-Related Protein 7
  • ATG3 protein, human