Department of Biology, Division of Immunology, University of Konstanz, 78457 Konstanz, Germany.
Department of Biology, University of Konstanz, 78457 Konstanz, Germany.
Cell Rep. 2021 Mar 16;34(11):108857. doi: 10.1016/j.celrep.2021.108857.
Parkin is an E3 ubiquitin ligase belonging to the RING-between-RING family. Mutations in the Parkin-encoding gene PARK2 are associated with familial Parkinson's disease. Here, we investigate the interplay between Parkin and the inflammatory cytokine-induced ubiquitin-like modifier FAT10. FAT10 targets hundreds of proteins for degradation by the 26S proteasome. We show that FAT10 gets conjugated to Parkin and mediates its degradation in a proteasome-dependent manner. Parkin binds to the E2 enzyme of FAT10 (USE1), auto-FAT10ylates itself, and facilitates FAT10ylation of the Parkin substrate Mitofusin2 in vitro and in cells, thus identifying Parkin as a FAT10 E3 ligase. On mitochondrial depolarization, FAT10ylation of Parkin inhibits its activation and ubiquitin-ligase activity causing impairment of mitophagy progression and aggravation of rotenone-mediated death of dopaminergic neuronal cells. In conclusion, FAT10ylation inhibits Parkin and mitophagy rendering FAT10 a likely inflammation-induced exacerbating factor and potential drug target for Parkinson's disease.
帕金是一种 E3 泛素连接酶，属于 RING 之间的 RING 家族。编码帕金基因 PARK2 的突变与家族性帕金森病有关。在这里，我们研究了帕金与炎症细胞因子诱导的泛素样修饰物 FAT10 之间的相互作用。FAT10 靶向数百种蛋白质通过 26S 蛋白酶体进行降解。我们表明 FAT10 与 Parkin 结合，并以蛋白酶体依赖的方式介导其降解。Parkin 结合到 FAT10 的 E2 酶 (USE1)，自身 FAT10 化，并促进 Mitofusin2 的 FAT10 化在体外和细胞中，从而将 Parkin 鉴定为 FAT10 E3 连接酶。在线粒体去极化时，Parkin 的 FAT10 化抑制其激活和泛素连接酶活性，导致线粒体自噬进展受损，并加剧鱼藤酮介导的多巴胺能神经元细胞死亡。总之，FAT10 化抑制 Parkin 和线粒体自噬，使 FAT10 成为炎症诱导的加重因素和帕金森病的潜在药物靶点。
