N端规则途径的N识别UBR4靶向于早期内体的生物发生，并为之需要。,Journal of Cell Science

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N端规则途径的N识别UBR4靶向于早期内体的生物发生，并为之需要。
Journal of Cell Science ( IF 3.3 ) Pub Date : 2018-09-10 , DOI: 10.1242/jcs.217646
Sung Tae Kim _{1,

2} , Yoon Jee Lee ₁ , Takafumi Tasaki _{3,

4} , Su Ran Mun ₁ , Joonsung Hwang ₅ , Min Jueng Kang ₆ , Srinivasrao Ganipisetti ₁ , Eugene C Yi ₆ , Bo Yeon Kim ₇ , Yong Tae Kwon _{8,

9}

Affiliation

Protein Metabolism Medical Research Center and Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul, 03080, Republic of Korea.
Center for Pharmacogenetics and Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, 15261, United States.
Division of Protein Regulation Research, Medical Research Institute, Kanazawa Medical University, Ishikawa, 920-0293, Japan.
Department of Medical Zoology, Kanazawa Medical University, Ishikawa, 920-0293, Japan.
World Class Institute, Anticancer Agents Research Center, Korea Research Institute of Bioscience and Biotechnology, Ochang, Cheongwon, 28116, Republic of Korea.
Department of Molecular Medicine and Biopharmaceutical Sciences, School of Convergence Science and Technology and College of Medicine or College of Pharmacy, Seoul National University, Seoul, 03080, Republic of Korea.
World Class Institute, Anticancer Agents Research Center, Korea Research Institute of Bioscience and Biotechnology, Ochang, Cheongwon, 28116, Republic of Korea
Protein Metabolism Medical Research Center and Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul, 03080, Republic of Korea
Ischemic/Hypoxic Disease Institute, College of Medicine, Seoul National University, Seoul 03080, Republic of Korea.

N端规则途径是一种蛋白水解系统，其中蛋白质的单个N末端残基充当N降解子。这些德隆被N-recognins识别，从而通过泛素（Ub）蛋白酶体系统（UPS）或自噬促进底物降解。我们之前已经确定了一组N-recognins [UBR1，UBR2，UBR4（也称为p600）和UBR5（也称为EDD）]，它们通过其UBR盒结合N-degrons，以促进蛋白酶体的蛋白水解。在这里，我们显示570 kDa N识别的UBR4通过与Ca2 +结合的钙调蛋白相互作用而与成熟的内体相关。UBR4的内体募集对于早期内体（EE）和内体相关过程（例如内吞水解酶的内吞蛋白货物的运输和胞外货物的降解）的生物发生至关重要。在小鼠胚胎中 UBR4标记并在内体-溶酶体途径中起作用，该途径介导将内吞的母体蛋白质异相蛋白水解为氨基酸。通过通过DrugBank数据库筛选9591种药物，我们确定了吡啶甲酸是UBR4的假定配体，UBR4抑制EEs的生物发生。我们的结果表明，UBR4是内体-溶酶体系统中必不可少的调节剂。本文对本文的第一作者进行了第一人称采访。

"点击查看英文标题和摘要"

The N-recognin UBR4 of the N-end rule pathway is targeted to and required for the biogenesis of the early endosome.

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.This article has an associated First Person interview with the first author of the paper.

更新日期：2019-11-01

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