ATG12 Conjugation to ATG3 Regulates Mitochondrial Homeostasis and Cell Death
Open accessAbstract
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.
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AMBRA1 and ATG12 positively regulate mitophagy.
“Although the role of ATG4A in mitophagy is unclear, AMBRA1 and ATG12 positively regulate mitophagy [56–58].”
From miR-27a and miR-27b regulate autophagic clearance of damaged mitochondria by targeting PTEN-induced putative kinase 1 (PINK1) (2016) · cites this paper as [58]
The Results (page unavailable) show that loss of ATG12 conjugation to ATG3 reduces mitochondrial targeting to autophagosomes during CCCP treatment, supporting a positive role for that complex in mitophagy. The paper does not address AMBRA1, so it does not support that part of the claim. (LLM, conf=0.90)
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“…ATG12 and ATG8 (ATG stands for autophagy regulator), play critical roles in macroautophagy (hereafter called autophagy), a tightly controlled lysosomal degradation process in which a cell digests its own proteins and organelles during starvation or stress (Levine and Kroemer, 2008; Ohsumi, 2001).”
The Atg12-Atg5 Conjugate Has a Novel E3-like Activity for Protein Lipidation in Autophagy
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“Although ATG12 and ATG8 possess little primary sequence homology to ubiquitin, both contain an ''ubiquitin superfold'' and the C-terminal glycine required for isopeptide linkage (Hanada and Ohsumi, 2005; Sugawara et al., 2004; Suzuki et al., 2005).”
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“A peptide corresponding to the N terminus common to human, mouse, and rat MAP1LC3 was used to create a-LC3 rabbit polyclonal antibody (Fung et al., 2008).”
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- Authors
- Radoshevich, L., Murrow, L., Chen, N., Fernandez, E., Roy, S., Fung, C., & Debnath, J.
- Affiliations
- University of California, San Francisco (US)
- Corresponding author
- Debnath, Jayanta
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2010-08
- Volume
- 142
- Issue
- 4
- Pages
- 590-600
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC2925044
- OpenAlex
- W2084067121
- Cited by
- 290
- References
- 8
- Citations by year
- 2026: 4 · 2025: 16 · 2024: 18 · 2023: 14 · 2022: 17 · 2021: 16 · 2020: 14 · 2019: 23 · 2018: 17 · 2017: 20 · 2016: 19 · 2015: 12 · 2014: 22 · 2013: 20 · 2012: 27
- FWCI
- 18.21
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Howard Hughes Medical Institute
- National Cancer Institute (K08CA098419, R01CA126792)
- Topics
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Keywords
- ATG12, ATG3, ubiquitin-like modification, ATG7, ATG5, macroautophagy, mitochondrial homeostasis, mitochondrial cell death, starvation-induced autophagy, E1 enzyme
- MeSH terms
- Autophagy-Related Proteins, Autophagy-Related Protein 5, Autophagy-Related Protein 12, Autophagy-Related Protein 7, Amino Acid Sequence, Autophagy, Cell Line, Embryo, Mammalian, Fibroblasts, HeLa Cells, Humans, Microtubule-Associated Proteins, Mitochondria, Molecular Sequence Data, Phagosomes, Proteins, Cell Death, Small Ubiquitin-Related Modifier Proteins, Ubiquitin-Conjugating Enzymes, Cell Line, Tumor
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