The N-recognin UBR4 of the N-end rule pathway is targeted to and required for the biogenesis of the early endosome
The N-recognin UBR4 of the N-end rule pathway is targeted to and required for the biogenesis of the early endosome
复制标题
DOI：
10.1242/jcs.217646
复制
发表时间：
2018-09-01
影响因子：
4
通讯作者：
Kwon, Yong Tae
中科院分区：
文献类型：
--
作者：
Kim, Sung Tae;Lee, Yoon Jee;Kwon, Yong Tae
N-末端规则途径是蛋白质的单个N-末端残基充当N-降解决定子的蛋白水解系统。这些降解决定子被N-识别蛋白识别，通过泛素（Ub）蛋白酶体系统（UPS）或自噬促进底物降解。我们之前已经鉴定了一组N-识别蛋白[UBR 1，UBR 2，UBR 4（也称为p600）和UBR 5（也称为EDD）]，它们通过其UBR盒结合N-降解决定子以促进蛋白酶体的蛋白水解。在这里，我们表明，570 kDa的N-识别UBR 4与成熟的内体通过与钙离子结合的钙调蛋白的相互作用。UBR 4的内体募集对于早期内体（EE）的生物发生和内体相关过程（例如内吞蛋白质货物的运输和内体水解酶对细胞外货物的降解）是必不可少的。在小鼠胚胎中，UBR 4标记内体-溶酶体途径并在该途径中起作用，该途径介导内吞的母体蛋白质的异噬蛋白水解成氨基酸。通过筛选9591药物通过DrugBank数据库，我们确定吡啶甲酸作为一个假定的配体UBR 4抑制EE的生物发生。我们的研究结果表明，UBR 4是一个重要的调制器内体-溶酶体系统。
The N-end rule pathway is a proteolytic system in which single N-terminal residues of proteins act as N-degrons. These degrons are recognized by N-recognins, facilitating substrate degradation via the ubiquitin (Ub) proteasome system (UPS) or autophagy. We have previously identified a set of N-recognins [UBR1, UBR2, UBR4 (also known as p600) and UBR5 (also known as EDD)] that bind N-degrons through their UBR boxes to promote proteolysis by the proteasome. Here, we show that the 570 kDa N-recognin UBR4 is associated with maturing endosomes through an interaction with Ca2+-bound calmodulin. The endosomal recruitment of UBR4 is essential for the biogenesis of early endosomes (EEs) and endosome-related processes, such as the trafficking of endocytosed protein cargos and degradation of extracellular cargos by endosomal hydrolases. In mouse embryos, UBR4 marks and plays a role in the endosome-lysosome pathway that mediates the heterophagic proteolysis of endocytosed maternal proteins into amino acids. By screening 9591 drugs through the DrugBank database, we identify picolinic acid as a putative ligand for UBR4 that inhibits the biogenesis of EEs. Our results suggest that UBR4 is an essential modulator in the endosome-lysosome system.