Ubiquitination independent of E1 and E2 enzymes by bacterial effectors.
Ubiquitination independent of E1 and E2 enzymes by bacterial effectors.
复制标题
细菌效应物的泛素化不依赖于 E1 和 E2 酶。
DOI：
10.1038/nature17657
复制
发表时间：
2016-05-05
期刊：
影响因子：
64.8
通讯作者：
Luo ZQ
中科院分区：
文献类型：
--
作者：
Qiu J;Sheedlo MJ;Yu K;Tan Y;Nakayasu ES;Das C;Liu X;Luo ZQ
在真核生物中，通过泛素化的信号转导几乎调节每一个细胞过程。泛素与底物的共价连接由E1、E2和E3三酶级联催化，其通过异肽键将泛素的C末端主要连接到底物赖氨酸的ε-氨基。鉴于泛素化在免疫系统调节中的重要作用，泛素化网络是各种感染因子的共同靶标也就不足为奇了。例如，许多细菌病原体使用毒力因子利用泛素信号传导，所述毒力因子充当E3连接酶、去泛素化酶或充当直接攻击泛素的酶。细菌病原体嗜肺军团菌利用大约300种效应物调节不同的宿主过程，以创建允许其在吞噬细胞中复制的小生境。在这里，我们证明了L.嗜肺菌泛素化与内质网（ER）相关的多个Rab小GTP酶。此外，我们表明，这些蛋白能够催化泛素化，而不需要E1和E2酶。一个推定的单ADP-核糖基转移酶（mART）基序的泛素化活性的关键也是必不可少的作用，在原生动物宿主的细胞内细菌复制的Sides。由这些酶催化的E1/E2非依赖性泛素化由NAD激活，NAD通过形成ADP-核糖基化泛素（ADPR-Ub）激活泛素。这些结果表明，泛素化可以由一种酶催化，其活性不需要ATP。
Signaling by ubiquitination regulates virtually every cellular process in eukaryotes. Covalent attachment of ubiquitin to a substrate is catalyzed by the E1, E2 and E3 three-enzyme cascade , which links the C terminus of ubiquitin via an isopeptide bond mostly to the ε-amino group of a lysine of the substrate. Given the essential roles of ubiquitination in the regulation of the immune system, it is not surprising that the ubiquitination network is a common target for diverse infectious agents . For example, many bacterial pathogens exploit ubiquitin signaling using virulence factors that function as E3 ligases, deubiquitinases or as enzymes that directly attack ubiquitin . The bacterial pathogen Legionella pneumophila utilizes approximately 300 effectors that modulate diverse host processes to create a niche permissive for its replication in phagocytes . Here we demonstrate that members of the SidE effector family (SidEs) of L. pneumophila ubiquitinate multiple Rab small GTPases associated with the endoplasmic reticulum (ER). Moreover, we show that these proteins are capable of catalyzing ubiquitination without the need for the E1 and E2 enzymes. A putative mono ADP-ribosyltransferase (mART) motif critical for the ubiquitination activity is also essential for the role of SidEs in intracellular bacterial replication in a protozoan host. The E1/E2-independent ubiquitination catalyzed by these enzymes is energized by NAD which activates ubiquitin by the formation of ADP-ribosylated ubiquitin (ADPR-Ub). These results establish that ubiquitination can be catalyzed by a single enzyme whose activity does not require ATP.