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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.

SUBMITTER: Haller M 

PROVIDER: S-EPMC4502749 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Ubiquitination and proteasomal degradation of ATG12 regulates its proapoptotic activity.

Haller Martina M   Hock Andreas K AK   Giampazolias Evangelos E   Oberst Andrew A   Green Douglas R DR   Debnath Jayanta J   Ryan Kevin M KM   Vousden Karen H KH   Tait Stephen W G SW  

Autophagy 20140101 12


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 ub  ...[more]

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