title: Ubiquitination and proteasomal degradation of ATG12 regulates its proapoptotic activity.
abstract: During macroautophagy, conjugation of ATG12 to ATG5 is essential for LC3 lipidation and autophagosome formation. Additionally, ATG12 has ATG5-independent functions in diverse processes including mitochondrial fusion and mitochondrial-dependent apoptosis. In this study, we investigated the regulation of free ATG12. In stark contrast to the stable ATG12-ATG5 conjugate, we find that free ATG12 is highly unstable and rapidly degraded in a proteasome-dependent manner. Surprisingly, ATG12, itself a ubiquitin-like protein, is directly ubiquitinated and this promotes its proteasomal degradation. As a functional consequence of its turnover, accumulation of free ATG12 contributes to proteasome inhibitor-mediated apoptosis, a finding that may be clinically important given the use of proteasome inhibitors as anticancer agents. Collectively, our results reveal a novel interconnection between autophagy, proteasome activity, and cell death mediated by the ubiquitin-like properties of ATG12.
authors: a Cancer Research UK Beatson Institute ; Glasgow , UK.
authors: Martina
authors: M
authors: Haller
authors: Andreas K
authors: AK
authors: Hock
authors: Evangelos
authors: E
authors: Giampazolias
authors: Andrew
authors: A
authors: Oberst
authors: Douglas R
authors: DR
authors: Green
authors: Jayanta
authors: J
authors: Debnath
authors: Kevin M
authors: KM
authors: Ryan
authors: Karen H
authors: KH
authors: Vousden
authors: Stephen W G
authors: SW
authors: Tait
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001343:Autophagy / Q000502:physiology*; D000071192:Autophagy-Related Protein 12; D016923:Cell Death / Q000502:physiology; D006801:Humans; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011499:Protein Processing, Post-Translational / Q000502:physiology; D025841:Small Ubiquitin-Related Modifier Proteins / Q000378:metabolism*; D044763:Ubiquitin-Conjugating Enzymes / Q000378:metabolism; D054875:Ubiquitination / Q000502:physiology*
chemical_list: C466624:ATG12 protein, human; D000071192:Autophagy-Related Protein 12; D008869:Microtubule-Associated Proteins; D025841:Small Ubiquitin-Related Modifier Proteins; D044763:Ubiquitin-Conjugating Enzymes; D046988:Proteasome Endopeptidase Complex
keywords: ATG, autophagy-related; ATG12; Act D, actinomycin D; BCL2L1, BCL2-like 1; BH3, BCL2 homology domain 3; CHX, cycloheximide; HBSS, Hank's balanced salt solution; LC3/MAP1LC3, microtubule-associated protein 1 light chain 3; MEF, mouse embryonic fibroblast; RNAi, RNA interference; UB, ubiquitin; UBL, ubiquitin-like protein; apoptosis; proteasomal degradation; ubiquitin-like protein; ubiquitination
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