Ubiquitination and proteasomal degradation of ATG12 regulates its proapoptotic activity |
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| Authors: | Martina Haller Andreas K Hock Evangelos Giampazolias Andrew Oberst Douglas R Green Jayanta Debnath Kevin M Ryan Karen H Vousden Stephen W G Tait |
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| Institution: | 1.Cancer Research UK Beatson Institute; Glasgow, UK;2.Institute of Cancer Sciences; University of Glasgow; Glasgow, UK;3.Department of Immunology; University of Washington; Seattle, WA USA;4.Department of Immunology; St. Jude Children''s Research Hospital; Memphis, TN USA;5.Department of Pathology and Helen Diller Family Comprehensive Cancer Center; University of California, San Francisco; San Francisco, CA USA |
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| 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. |
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| Keywords: | apoptosis ATG12 proteasomal degradation ubiquitin-like protein ubiquitination |
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