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ATG12 conjugation to ATG3 regulates mitochondrial homeostasis and cell death.

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.

Pubmed ID: 20723759


  • Radoshevich L
  • Murrow L
  • Chen N
  • Fernandez E
  • Roy S
  • Fung C
  • Debnath J



Publication Data

August 20, 2010

Associated Grants

  • Agency: NCI NIH HHS, Id: K08 CA098419
  • Agency: NCI NIH HHS, Id: K08 CA098419-06
  • Agency: NCI NIH HHS, Id: K08CA098419
  • Agency: NCI NIH HHS, Id: R01 CA126792
  • Agency: NCI NIH HHS, Id: R01 CA126792-02
  • Agency: NCI NIH HHS, Id: R01CA126792
  • Agency: Howard Hughes Medical Institute, Id:

Mesh Terms

  • Amino Acid Sequence
  • Autophagy
  • Cell Death
  • Cell Line
  • Cell Line, Tumor
  • Embryo, Mammalian
  • Fibroblasts
  • HeLa Cells
  • Humans
  • Microtubule-Associated Proteins
  • Mitochondria
  • Molecular Sequence Data
  • Phagosomes
  • Proteins
  • Small Ubiquitin-Related Modifier Proteins
  • Ubiquitin-Conjugating Enzymes