Mechanism of Lys6 poly-ubiquitin specificity by the L. pneumophila deubiquitinase LotA.
Mechanism of Lys6 poly-ubiquitin specificity by the L. pneumophila deubiquitinase LotA.
复制标题
嗜肺军团菌去泛素酶 LotA 的 Lys6 多泛素特异性机制。
DOI：
10.1016/j.molcel.2022.11.022
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发表时间：
2023
期刊：
影响因子：
16
通讯作者：
Pruneda JN.
中科院分区：
文献类型：
--
作者：
Warren GD;Kitao T;Franklin TG;Nguyen JV;Geurink PP;Kubori T;Nagai H;Pruneda JN.
泛素化的多功能性，以控制真核生物学的广阔领域，部分是由于多样化，通过不同的连接聚泛素链。一些链类型（包括通过K6连接的链）的破译信号作用一直受到相关调节蛋白之间缺乏特异性的阻碍。在强大的进化压力下，致病菌进化出了复杂的机制来调节宿主在感染过程中的泛素。在这里，我们确定和表征的分泌效应LotA从嗜肺军团菌特异性调节K6连接的多聚泛素的去泛素化酶结构域。我们证明了LotA用于研究K6聚泛素信号的实用性。我们确定了LotA激活和多聚泛素特异性的结构基础，并描述了一个重要的“自适应”泛素结合结构域。在感染过程中没有LotA活性，含有军团菌的空泡被K6多聚泛素以及AAA ATP酶VCP/p97/Cdc 48修饰。我们认为LotA的去泛素化酶活性保护了含军团菌的液泡成分不受泛素依赖性提取的影响。
The versatility of ubiquitination to control vast domains of eukaryotic biology is due, in part, to diversification through differently linked poly-ubiquitin chains. Deciphering signaling roles for some chain types, including those linked via K6, has been stymied by a lack of specificity among the implicated regulatory proteins. Forged through strong evolutionary pressures, pathogenic bacteria have evolved intricate mechanisms to regulate host ubiquitin during infection. Herein, we identify and characterize a deubiquitinase domain of the secreted effector LotA fromLegionella pneumophilathat specifically regulates K6-linked poly-ubiquitin. We demonstrate the utility of LotA for studying K6 poly-ubiquitin signals. We identify the structural basis of LotA activation and poly-ubiquitin specificity and describe an essential "adaptive" ubiquitin-binding domain. Without LotA activity during infection, theLegionella-containing vacuole becomes decorated with K6 poly-ubiquitin as well as the AAA ATPase VCP/p97/Cdc48. We propose that LotA's deubiquitinase activity guardsLegionella-containing vacuole components from ubiquitin-dependent extraction.