Günter Julia, Ruiz-Serrano Amalia, Pickel Christina, Wenger Roland H, Scholz Carsten C
Institute of Physiology, University of Zurich, 8057 Zurich, Switzerland.
Institute of Physiology, University of Zurich, 8057 Zurich, Switzerland.
Exp Cell Res. 2017 Jul 15;356(2):152-159. doi: 10.1016/j.yexcr.2017.03.027. Epub 2017 Mar 15.
The hypoxia inducible factor (HIF) pathway and the ubiquitin system represent major cellular processes that are involved in the regulation of a plethora of cellular signaling pathways and tissue functions. The ubiquitin system controls the ubiquitination of proteins, which is the covalent linkage of one or several ubiquitin molecules to specific targets. This ubiquitination is catalyzed by approximately 1000 different E3 ubiquitin ligases and can lead to different effects, depending on the type of internal ubiquitin chain linkage. The best-studied function is the targeting of proteins for proteasomal degradation. The activity of E3 ligases is antagonized by proteins called deubiquitinases (or deubiquitinating enzymes), which negatively regulate ubiquitin chains. This is performed in most cases by the catalytic removal of these chains from the targeted protein. The HIF pathway is regulated in an oxygen-dependent manner by oxygen-sensing hydroxylases. Covalent modification of HIFα subunits leads to the recruitment of an E3 ligase complex via the von Hippel-Lindau (VHL) protein and the subsequent polyubiquitination and proteasomal degradation of HIFα subunits, demonstrating the regulation of the HIF pathway by the ubiquitin system. This unidirectional effect of an E3 ligase on the HIF pathway is the best-studied example for the interplay between these two important cellular processes. However, additional regulatory mechanisms of the HIF pathway through the ubiquitin system are emerging and, more recently, also the reciprocal regulation of the ubiquitin system through components of the HIF pathway. Understanding these mechanisms and their relevance for the activity of each other is of major importance for the comprehensive elucidation of the oxygen-dependent regulation of cellular processes. This review describes the current knowledge of the functional bidirectional interplay between the HIF pathway and the ubiquitin system on the protein level.
缺氧诱导因子（HIF）通路和泛素系统是主要的细胞过程，参与众多细胞信号通路和组织功能的调节。泛素系统控制蛋白质的泛素化，即一个或几个泛素分子与特定靶标的共价连接。这种泛素化由大约1000种不同的E3泛素连接酶催化，根据内部泛素链连接的类型可导致不同的效应。研究最深入的功能是将蛋白质靶向蛋白酶体降解。E3连接酶的活性受到称为去泛素酶（或去泛素化酶）的蛋白质的拮抗，这些蛋白质对泛素链进行负调节。在大多数情况下，这是通过从靶蛋白上催化去除这些链来实现的。HIF通路由氧感应羟化酶以氧依赖的方式调节。HIFα亚基的共价修饰通过冯·希佩尔-林道（VHL）蛋白导致E3连接酶复合物的募集，随后HIFα亚基发生多聚泛素化和蛋白酶体降解，这表明泛素系统对HIF通路的调节。E3连接酶对HIF通路的这种单向作用是这两个重要细胞过程之间相互作用的研究最深入的例子。然而，通过泛素系统对HIF通路的其他调节机制正在出现，最近，通过HIF通路的组分对泛素系统的反向调节也在出现。了解这些机制及其相互之间的相关性对于全面阐明细胞过程的氧依赖调节至关重要。本综述描述了目前关于HIF通路和泛素系统在蛋白质水平上功能双向相互作用的知识。
