SidJ-钙调蛋白催化的谷氨酸化抑制细菌泛素连接酶，这一成果由德国歌德大学Ivan Dikic、 Sagar Bhogaraju研究团队取得。该论文发表在2019年8月15日出版的国际学术期刊《自然》上。

研究人员发现SidJ是谷氨酸化酶，其修饰SdeA的单-ADP核糖基转移酶结构域中的催化性谷氨酸，从而阻断SdeA的泛素连接酶活性。SidJ的谷氨酸化活性需要与真核特异性辅因子钙调蛋白相互作用，并且可以通过Ca²⁺浓度的细胞内变化来调节。与人apo-钙调蛋白复合的SidJ冷冻电镜结构揭示了这种异二聚体谷氨酸化酶的结构。研究人员发现在感染嗜肺军团菌的细胞中，SidJ介导含有军团菌的液泡表面上SidE酶的谷氨酸化。研究人员使用定量蛋白质组学揭示了多种宿主蛋白作为SidJ介导的谷氨酸化的可能靶标。这项研究揭示了SidE-钙调蛋白谷氨酸化酶抑制SidE连接酶的机制，并为探索真核生物中未经研究的蛋白质修饰（谷氨酸化）开辟了途径。

据悉，细菌SidE酶家族催化磷酸核糖基连接的丝氨酸泛素化并促进嗜肺军团菌的感染性，嗜肺军团菌是导致军团病的病原菌。SidE酶与军团菌效应蛋白SidJ共享遗传基因座，并以目前未知的机制抑制这些酶在酵母和哺乳动物细胞中的毒性。SidJ的缺失导致军团菌在其天然宿主（变形虫）和小鼠巨噬细胞中的生长发生严重缺陷。

附：英文原文

Title: Inhibition of bacterial ubiquitin ligases by SidJ–calmodulin catalysed glutamylation

Author: Sagar Bhogaraju, Florian Bonn, Rukmini Mukherjee, Michael Adams, Moritz M. Pfleiderer, Wojciech P. Galej, Vigor Matkovic, Jaime Lopez-Mosqueda, Sissy Kalayil, Donghyuk Shin, Ivan Dikic

Issue&Volume: Volume 572 Issue 7769

Abstract: The family of bacterial SidE enzymes catalyses phosphoribosyl-linked serine ubiquitination and promotes infectivity of Legionella pneumophila, a pathogenic bacteria that causes Legionnaires disease13. SidE enzymes share the genetic locus with the Legionella effector SidJ that spatiotemporally opposes the toxicity of these enzymes in yeast and mammalian cells, through a mechanism that is currently unknown46. Deletion of SidJ leads to a substantial defect in the growth of Legionella in both its natural hosts (amoebae) and in mouse macrophages4,5. Here we demonstrate that SidJ is a glutamylase that modifies the catalytic glutamate in the mono-ADP ribosyl transferase domain of the SdeA, thus blocking the ubiquitin ligase activity of SdeA. The glutamylation activity of SidJ requires interaction with the eukaryotic-specific co-factor calmodulin, and can be regulated by intracellular changes in Ca2+ concentrations. The cryo-electron microscopy structure of SidJ in complex with human apo-calmodulin revealed the architecture of this heterodimeric glutamylase. We show that, in cells infected with L. pneumophila, SidJ mediates the glutamylation of SidE enzymes on the surface of vacuoles that contain Legionella. We used quantitative proteomics to uncover multiple host proteins as putative targets of SidJ-mediated glutamylation. Our study reveals the mechanism by which SidE ligases are inhibited by a SidJcalmodulin glutamylase, and opens avenues for exploring an understudied protein modification (glutamylation) in eukaryotes.

DOI: 10.1038/s41586-019-1440-8

Source:https://www.nature.com/articles/s41586-019-1440-8