title: Acetylation of Lysine 201 Inhibits the DNA-Binding Ability of PhoP to Regulate Salmonella Virulence.
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.
authors.affiliation: Laboratory of Bacterial Pathogenesis, Department of Microbiology and Immunology, Institutes of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Ren
authors.affiliation: Laboratory of Bacterial Pathogenesis, Department of Microbiology and Immunology, Institutes of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Sang
authors.affiliation: Laboratory of Bacterial Pathogenesis, Department of Microbiology and Immunology, Institutes of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Yongcong
authors.initials: Y
authors.lastname: Tan
authors.affiliation: Laboratory of Bacterial Pathogenesis, Department of Microbiology and Immunology, Institutes of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Tao
authors.affiliation: Laboratory of Bacterial Pathogenesis, Department of Microbiology and Immunology, Institutes of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Jinjing
authors.initials: J
authors.lastname: Ni
authors.affiliation: Laboratory of Bacterial Pathogenesis, Department of Microbiology and Immunology, Institutes of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Shuting
authors.initials: S
authors.lastname: Liu
authors.affiliation: Laboratory of Bacterial Pathogenesis, Department of Microbiology and Immunology, Institutes of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Xia
authors.initials: X
authors.lastname: Fan
authors.affiliation: Laboratory of Bacterial Pathogenesis, Department of Microbiology and Immunology, Institutes of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhao
authors.affiliation: Department of Infectious Diseases, Shanghai Ruijin Hospital, Shanghai, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Lu
authors.affiliation: Department of Laboratory Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: Wenjuan
authors.initials: W
authors.lastname: Wu
authors.affiliation: Laboratory of Bacterial Pathogenesis, Department of Microbiology and Immunology, Institutes of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, China.|Department of Laboratory Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: Yu-Feng
authors.initials: YF
authors.lastname: Yao
mesh_terms: D000107:Acetylation; D000595:Amino Acid Sequence; D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins; D004195:Disease Models, Animal; D015964:Gene Expression Regulation, Bacterial; D006801:Humans; D008239:Lysine / Q000737:chemistry; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D010587:Phagocytosis; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D012480:Salmonella Infections / Q000276:immunology* / Q000382:microbiology; D012486:Salmonella typhimurium / Q000235:genetics / Q000276:immunology / Q000472:pathogenicity*; D016415:Sequence Alignment; D017384:Sequence Deletion; D014774:Virulence
chemical_list: D001426:Bacterial Proteins; D004268:DNA-Binding Proteins; C079792:PhoQ protein, Bacteria; C061064:PhoP protein, Bacteria; D008239:Lysine