Striebel Frank, Imkamp Frank, Özcelik Dennis, Weber-Ban Eilika
Max Planck Institute of Biochemistry, Department of Molecular Cell Biology, D-82152 Martinsried, Germany.
Biochim Biophys Acta. 2014 Jan;1843(1):103-13. doi: 10.1016/j.bbamcr.2013.03.022. Epub 2013 Apr 2.
Posttranslational modifications in the form of covalently attached proteins like ubiquitin (Ub), were long considered an exclusive feature of eukaryotic organisms. The discovery of pupylation, the modification of lysine residues with a prokaryotic, ubiquitin-like protein (Pup), demonstrated that certain bacteria use a tagging pathway functionally related to ubiquitination in order to target proteins for proteasomal degradation. However, functional analogies do not translate into structural or mechanistic relatedness. Bacterial Pup, unlike eukaryotic Ub, does not adopt a β-grasp fold, but is intrinsically disordered. Furthermore, isopeptide bond formation in the pupylation process is carried out by enzymes evolutionary descendent from glutamine synthetases. While in eukaryotes, the proteasome is the main energy-dependent protein degradation machine, bacterial proteasomes exist in addition to other architecturally related degradation complexes, and their specific role along with the role of pupylation is still poorly understood. In Mycobacterium tuberculosis (Mtb), the Pup-proteasome system contributes to pathogenicity by supporting the bacterium's persistence within host macrophages. Here, we describe the mechanism and structural framework of pupylation and the targeting of pupylated proteins to the proteasome complex. Particular attention is given to the comparison of the bacterial Pup-proteasome system and the eukaryotic ubiquitin-proteasome system. Furthermore, the involvement of pupylation and proteasomal degradation in Mtb pathogenesis is discussed together with efforts to establish the Pup-proteasome system as a drug target. This article is part of a Special Issue entitled: Ubiquitin-Proteasome System. Guest Editors: Thomas Sommer and Dieter H. Wolf.
以共价连接的蛋白质（如泛素，Ub）形式存在的翻译后修饰，长期以来被认为是真核生物独有的特征。原核泛素样蛋白（Pup）对赖氨酸残基进行修饰的“pupylation”的发现表明，某些细菌使用一种与泛素化功能相关的标记途径，以便将蛋白质靶向蛋白酶体降解。然而，功能上的相似性并不意味着结构或机制上的相关性。与真核生物的Ub不同，细菌的Pup不具有β-抓握折叠结构，而是内在无序的。此外，pupylation过程中的异肽键形成是由谷氨酰胺合成酶进化而来的酶进行的。在真核生物中，蛋白酶体是主要的能量依赖型蛋白质降解机器，而细菌除了其他结构相关的降解复合物外还存在蛋白酶体，其具体作用以及pupylation的作用仍知之甚少。在结核分枝杆菌（Mtb）中，Pup-蛋白酶体系统通过支持细菌在宿主巨噬细胞内的存活而促进致病性。在这里，我们描述了pupylation的机制和结构框架以及pupylated蛋白靶向蛋白酶体复合物的过程。特别关注细菌Pup-蛋白酶体系统与真核泛素-蛋白酶体系统的比较。此外，还讨论了pupylation和蛋白酶体降解在Mtb发病机制中的作用，以及将Pup-蛋白酶体系统确立为药物靶点的努力。本文是名为：泛素-蛋白酶体系统的特刊的一部分。客座编辑：Thomas Sommer和Dieter H. Wolf。
