Abstract
The two-component system PhoP-PhoQ is highly conserved in bacteria and regulates virulence in response to various signals for bacteria within the mammalian host. Here, we demonstrate that PhoP could be acetylated by Pat and deacetylated by deacetylase CobB enzymatically in vitro and in vivo in Salmonella Typhimurium. Specifically, the conserved lysine residue 201(K201) in winged helix–turn–helix motif at C-terminal DNA-binding domain of PhoP could be acetylated, and its acetylation level decreases dramatically when bacteria encounter low magnesium, acid stress or phagocytosis of macrophages. PhoP has a decreased acetylation and increased DNA-binding ability in the deletion mutant of pat. However, acetylation of K201 does not counteract PhoP phosphorylation, which is essential for PhoP activity. In addition, acetylation of K201 (mimicked by glutamine substitute) in S. Typhimurium causes significantly attenuated intestinal inflammation as well as systemic infection in mouse model, suggesting that deacetylation of PhoP K201 is essential for Salmonella pathogenesis. Therefore, we propose that the reversible acetylation of PhoP K201 may ensure Salmonella promptly respond to different stresses in host cells. These findings suggest that reversible lysine acetylation in the DNA-binding domain, as a novel regulatory mechanism of gene expression, is involved in bacterial virulence across microorganisms.
Highlights
As Gram-negative bacteria, salmonellae can cause enteric diseases in a wide range of animals
We show that PhoP can be acetylated by the protein acetyltransferase Pat, or deacetylated by the nicotinamide adenine dinucleotide (NAD)-dependent deacetylase CobB
Control of protein function by reversible Nε-Lys acetylation is conserved in both eukaryotes and bacteria [24, 29].Proteomic analysis showed that PhoP was acetylated [21], we want to confirm the observation and determine the mechanism(s) by which PhoP becomes acetylated
Summary
As Gram-negative bacteria, salmonellae can cause enteric diseases in a wide range of animals. Salmonella Typhimurium, non-typhoidal Salmonella (NTS), is usually used as a model organism to understand bacterial interactions with host cells. Salmonella can survive and multiply inside several mammalian cell types, including epithelial cells and macrophages [1, 2]. The intracellular Salmonella within either epithelial cells or macrophages could escape from neutrophil-mediated killing, which is critical for pathogenesis. Salmonella has evolved a plethora of regulatory circuits that facilitate them to adapt to different environments. PhoP-PhoQ is one such two-component system that has been identified in several bacteria, including Salmonella [3], Yersinia pestis [4], and Pseudomonas aeruginosa [5]
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