浙江大学朱永群等研究人员合作发现，军团菌效应物LnaB是一种可损害磷酸信号传递的磷酸腺苷化酶。相关论文于2024年5月22日在线发表在《自然》杂志上。

研究人员发现，以ATP为配体，以肌动蛋白为宿主激活剂，嗜肺军团菌的效应蛋白LnaB对PR^R42-Ub上的磷酸核糖的磷酸基团表现出腺苷酸化酶活性，该磷酸基团由SidE家族效应蛋白和去泛素化酶DupA/B在不依赖于E1/E2的泛素化过程中生成。LnaB的产物会被ADP-ribosyl水解酶MavL进一步水解为Ub，从而防止PR^R42-Ub和ADPR^R42-Ub的积累，保护宿主细胞中的经典泛素化。

LnaB代表了一个庞大的腺苷酸化酶家族，在20多种细菌病原体中采用共同的结构折叠，有别于之前已知的腺苷酸化酶。此外，LnaB还对磷酸化残基表现出强大的磷酸化腺苷酸化酶活性，并在蛋白质中产生独特的腺苷酸化修饰。在感染过程中，LnaB腺苷酸化Src家族激酶激活环中保守的磷酸化酪氨酸残基，从而抑制宿主的下游磷酸化信号传导。

结构研究揭示了LnaB腺苷酸化酶家族的肌动蛋白依赖性激活和催化机制。这项研究展现了细菌致病和蛋白质磷酸化过程中前所未有的调控和分子机制。

据了解，腺苷酸化是一种翻译后修饰，通常是用单磷酸腺苷（AMP）修饰蛋白质的氨基酸侧链。

附：英文原文

Title: Legionella effector LnaB is a phosphoryl-AMPylase that impairs phosphosignalling

Author: Wang, Ting, Song, Xiaonan, Tan, Jiaxing, Xian, Wei, Zhou, Xingtong, Yu, Mingru, Wang, Xiaofei, Xu, Yan, Wu, Ting, Yuan, Keke, Ran, Yu, Yang, Bing, Fan, Gaofeng, Liu, Xiaoyun, Zhou, Yan, Zhu, Yongqun

Issue&Volume: 2024-05-22

Abstract: AMPylation is a posttranslational modification that generally modifies amino acid side chains of proteins with adenosine monophosphate (AMP)1,2. Here we report that with ATP as the ligand and actin as the host activator, the effector protein LnaB of Legionella pneumophila exhibits AMPylase activity toward the phosphoryl group of phosphoribose on PRR42-Ub that is generated by the SidE family effectors and deubiquitinases DupA/B in an E1/E2-independent ubiquitination process3-7. The product of LnaB is further hydrolyzed by an ADP-ribosyl hydrolase, MavL, to be Ub, thereby preventing accumulation of PRR42-Ub and ADPRR42-Ub and protecting the canonical ubiquitination in host cells. LnaB represents a large family of AMPylases adopting a common structural fold, which is distinct from those of the previously known AMPylases, in bacterial pathogens of more than 20 species. Moreover, LnaB also exhibits robust phosphoryl AMPylase activity toward phosphorylated residues and produces unique ADPylation modification in proteins. During infection, LnaB AMPylates the conserved phosphorylated tyrosine residues in the activation loop of the Src family kinases8,9, which dampens the host downstream phosphorylation signaling. Structural studies revealed the actin-dependent activation and catalytic mechanisms of the LnaB family of AMPylases. This study presents an unprecedented regulation and molecular mechanism in bacterial pathogenesis and protein phosphorylation.

DOI: 10.1038/s41586-024-07573-z

Source: https://www.nature.com/articles/s41586-024-07573-z