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.
Copyright 2010 Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Sequence
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Autophagy
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Autophagy-Related Protein 12
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Autophagy-Related Protein 5
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Autophagy-Related Protein 7
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Autophagy-Related Proteins
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Cell Death*
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Cell Line
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Cell Line, Tumor
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Embryo, Mammalian / cytology
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Fibroblasts / metabolism
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HeLa Cells
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Humans
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Microtubule-Associated Proteins / metabolism
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Mitochondria / metabolism*
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Molecular Sequence Data
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Phagosomes / metabolism
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Proteins / chemistry
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Proteins / metabolism
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Small Ubiquitin-Related Modifier Proteins / chemistry
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Small Ubiquitin-Related Modifier Proteins / metabolism*
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Ubiquitin-Conjugating Enzymes / chemistry
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Ubiquitin-Conjugating Enzymes / metabolism*
Substances
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ATG12 protein, human
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ATG5 protein, human
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Atg12 protein, mouse
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Atg7 protein, mouse
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Autophagy-Related Protein 12
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Autophagy-Related Protein 5
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Autophagy-Related Proteins
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Microtubule-Associated Proteins
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Proteins
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Small Ubiquitin-Related Modifier Proteins
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Ubiquitin-Conjugating Enzymes
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Autophagy-Related Protein 7
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ATG3 protein, human