Acetylation of Lysine 201 Inhibits the DNA-Binding Ability of PhoP to Regulate Salmonella Virulence

• Published in: PLoS pathogens Vol. 12; no. 3; p. e1005458
• Main Authors: Ren, Jie, Sang, Yu, Tan, Yongcong, Tao, Jing, Ni, Jinjing, Liu, Shuting, Fan, Xia, Zhao, Wei, Lu, Jie, Wu, Wenjuan, Yao, Yu-Feng
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01-03-2016; Public Library of Science (PLoS)
• Subjects: Acetylation; Amino Acid Sequence; Analysis; Animals; Bacteria; Bacterial Proteins - genetics; Bacterial Proteins - metabolism; Biology and Life Sciences; Chromosomes; Deoxyribonucleic acid; Disease Models, Animal; DNA; DNA binding; DNA-Binding Proteins; Gene expression; Gene Expression Regulation, Bacterial; Genetic aspects; Genetic engineering; Humans; Kinases; Lysine; Lysine - chemistry; Macrophages - metabolism; Medicine and Health Sciences; Methods; Mice; Molecular Sequence Data; Pathogenesis; Phagocytosis; Phosphorylation; Physical Sciences; Protein Structure, Tertiary; Proteins; Research and Analysis Methods; RNA polymerase; Salmonella; Salmonella Infections - immunology; Salmonella Infections - microbiology; Salmonella typhimurium; Salmonella typhimurium - genetics; Salmonella typhimurium - immunology; Salmonella typhimurium - pathogenicity; Sequence Alignment; Sequence Deletion; Signal transduction; Virulence; Virulence (Microbiology)
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1005458

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.