Jiao H, Su G-Q, Dong W, Zhang L, Xie W, Yao L-M, Chen P, Wang Z-X, Liou Y-C, You H
State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China.
Department of General Surgery, The First Affiliated Hospital of Xiamen University, Xiamen, Fujian 361003, China.
Cell Death Differ. 2015 Nov;22(11):1812-23. doi: 10.1038/cdd.2015.34. Epub 2015 Apr 23.
Mitophagy mediates clearance of dysfunctional mitochondria, and represents one type of mitochondrial quality control, which is essential for optimal mitochondrial bioenergetics. p32, a chaperone-like protein, is crucial for maintaining mitochondrial membrane potential and oxidative phosphorylation. However, the relationship between p32 and mitochondrial homeostasis has not been addressed. Here, we identified p32 as a key regulator of ULK1 stability by forming complex with ULK1. p32 depletion potentiated K48-linked but impaired K63-linked polyubiquitination of ULK1, leading to proteasome-mediated degradation of ULK1. As a result, silencing p32 profoundly impaired starvation-induced autophagic flux and the clearance of damaged mitochondria caused by mitochondrial uncoupler. Importantly, restoring ULK1 expression in p32-depleted cells rescued autophagy and mitophagy defects. Our findings highlight a cytoprotective role of p32 under starvation conditions by regulating ULK1 stability, and uncover a crucial role of the p32-ULK1-autophagy axis in coordinating stress response, cell survival and mitochondrial homeostasis.
线粒体自噬介导功能失调线粒体的清除，是线粒体质量控制的一种类型，对最佳线粒体生物能量学至关重要。p32是一种类似伴侣蛋白，对维持线粒体膜电位和氧化磷酸化至关重要。然而，p32与线粒体稳态之间的关系尚未得到探讨。在此，我们通过与ULK1形成复合物，确定p32是ULK1稳定性的关键调节因子。p32缺失增强了ULK1的K48连接的多聚泛素化，但损害了K63连接的多聚泛素化，导致蛋白酶体介导的ULK1降解。结果，沉默p32严重损害饥饿诱导的自噬通量以及线粒体解偶联剂引起的受损线粒体的清除。重要的是，在p32缺失的细胞中恢复ULK1表达可挽救自噬和线粒体自噬缺陷。我们的研究结果突出了p32在饥饿条件下通过调节ULK1稳定性发挥的细胞保护作用，并揭示了p32-ULK1-自噬轴在协调应激反应、细胞存活和线粒体稳态中的关键作用。
