Haller Martina, Hock Andreas K, Giampazolias Evangelos, Oberst Andrew, Green Douglas R, Debnath Jayanta, Ryan Kevin M, Vousden Karen H, Tait Stephen W G
a Cancer Research UK Beatson Institute ; Glasgow , UK.
Autophagy. 2014;10(12):2269-78. doi: 10.4161/15548627.2014.981914.
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.
在巨自噬过程中，ATG12与ATG5的结合对于LC3脂化和自噬体形成至关重要。此外，ATG12在包括线粒体融合和线粒体依赖性凋亡在内的多种过程中具有不依赖ATG5的功能。在本研究中，我们研究了游离ATG12的调控。与稳定的ATG12-ATG5共轭物形成鲜明对比的是，我们发现游离ATG12高度不稳定，并以蛋白酶体依赖性方式迅速降解。令人惊讶的是，ATG12本身是一种类泛素蛋白，可直接被泛素化，这促进了其蛋白酶体降解。作为其周转的功能后果，游离ATG12的积累导致蛋白酶体抑制剂介导的细胞凋亡，鉴于蛋白酶体抑制剂作为抗癌药物的应用，这一发现可能具有临床重要性。总的来说，我们的结果揭示了自噬、蛋白酶体活性和由ATG12的类泛素特性介导的细胞死亡之间的一种新型联系。
