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Legionella effector LnaB is a phosphoryl-AMPylase that impairs phosphosignalling

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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.

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Correspondence to Xiaoyun Liu, Yan Zhou or Yongqun Zhu.

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Supplementary Figure 1

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Reporting Summary

Supplementary Table 1

The LnaB homologues and genomic analyses of the LnaB homologue-encoded bacterial strains. The locus of the 162 LnaB homologues in the bacterial genomes are listed as indicated. LnaB is highlighted in red in the list. The homolgoues of MavL and SidEs are also examined in the bacterial strains. The signal peptides of the type 3, 4 and 6 secretion systems in the LnaB homologuess’ sequences were predicted using th program DeepT3 v2.0, the T4SEfinder web server (https://tool2-mml.sjtu.edu.cn/T4SEfinder_TAPE/), Bastion6 web server (https://bastion6.erc.monash.edu/), and DeepSecE web server (https://tool2-mml.sjtu.edu.cn/DeepSecEdb/), respectively. Type 3, 4 and 6 secretion systems in the LnaB homologue-containing bacterial strains are analyzed, according to the conserve type 3 secretion system components SctC, SctJ, and ATPase SctN4, type 4 secretion system components VirD4 and VirB45-7, and type 6 secretion system components TssB and TssC, respectively.

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Wang, T., Song, X., Tan, J. et al. Legionella effector LnaB is a phosphoryl-AMPylase that impairs phosphosignalling. Nature (2024). https://doi.org/10.1038/s41586-024-07573-z

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  • DOI: https://doi.org/10.1038/s41586-024-07573-z

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