Division of Biology, California Institute of Technology, Pasadena, CA 91125, USA.
Hum Mol Genet. 2011 May 1;20(9):1726-37. doi: 10.1093/hmg/ddr048. Epub 2011 Feb 4.
Parkin, an E3 ubiquitin ligase implicated in Parkinson's disease, promotes degradation of dysfunctional mitochondria by autophagy. Using proteomic and cellular approaches, we show that upon translocation to mitochondria, Parkin activates the ubiquitin-proteasome system (UPS) for widespread degradation of outer membrane proteins. This is evidenced by an increase in K48-linked polyubiquitin on mitochondria, recruitment of the 26S proteasome and rapid degradation of multiple outer membrane proteins. The degradation of proteins by the UPS occurs independently of the autophagy pathway, and inhibition of the 26S proteasome completely abrogates Parkin-mediated mitophagy in HeLa, SH-SY5Y and mouse cells. Although the mitofusins Mfn1 and Mfn2 are rapid degradation targets of Parkin, we find that degradation of additional targets is essential for mitophagy. These results indicate that remodeling of the mitochondrial outer membrane proteome is important for mitophagy, and reveal a causal link between the UPS and autophagy, the major pathways for degradation of intracellular substrates.
Parkin 是一种与帕金森病相关的 E3 泛素连接酶，可通过自噬促进功能失调的线粒体降解。我们使用蛋白质组学和细胞方法表明，Parkin 一旦转移到线粒体，就会激活泛素-蛋白酶体系统（UPS），广泛降解外膜蛋白。这可以通过线粒体上 K48 连接的多聚泛素的增加、26S 蛋白酶体的募集以及多种外膜蛋白的快速降解来证明。UPS 对蛋白质的降解独立于自噬途径，并且抑制 26S 蛋白酶体完全消除了 HeLa、SH-SY5Y 和小鼠细胞中 Parkin 介导的线粒体自噬。尽管线粒体融合蛋白 Mfn1 和 Mfn2 是 Parkin 的快速降解靶标，但我们发现其他靶标的降解对于线粒体自噬是必不可少的。这些结果表明线粒体外膜蛋白质组的重塑对于线粒体自噬很重要，并揭示了 UPS 和自噬之间的因果关系，自噬是细胞内底物降解的主要途径。
