Ubiquitination and proteasomal degradation of ATG12 regulates its proapoptotic activity.
Ubiquitination and proteasomal degradation of ATG12 regulates its proapoptotic activity.
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DOI：
10.4161/15548627.2014.981914
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发表时间：
2014
期刊：
影响因子：
13.3
通讯作者：
Tait SW
中科院分区：
文献类型：
--
作者：
Haller M;Hock AK;Giampazolias E;Oberst A;Green DR;Debnath J;Ryan KM;Vousden KH;Tait SW
在巨自噬过程中，ATG 12与ATG 5的缀合对于LC 3脂化和自噬体形成是必不可少的。此外，ATG 12在包括线粒体融合和细胞依赖性凋亡在内的多种过程中具有ATG 5非依赖性功能。在这项研究中，我们研究了游离ATG 12的调节。与稳定的ATG 12-ATG 5缀合物形成鲜明对比，我们发现游离的ATG 12是高度不稳定的，并且以蛋白酶体依赖性方式快速降解。令人惊讶的是，ATG 12本身是一种泛素样蛋白，直接被泛素化，这促进了它的蛋白酶体降解。作为其周转的功能性结果，游离ATG 12的积累有助于蛋白酶体转运蛋白介导的细胞凋亡，这一发现在使用蛋白酶体抑制剂作为抗癌剂时可能具有临床重要性。总的来说，我们的研究结果揭示了自噬，蛋白酶体活性和细胞死亡之间的一种新的相互联系，由ATG 12的泛素样特性介导。
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.