The Role Of Acetylation In Regulating PhoP Activity And Salmonella Virulence

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.In pat deletion mutant,PhoP had decreased acetylation and increased DNA-binding ability.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 caused significantly attenuated intestinal inflammation as well as systemic infection in mouse model,suggesting that deacetylation of PhoP K201 is essential for Salmonella pathogenesis.Addtionally,PhoP can also be acetylated by small molecular acetyl phosphate AcP both in vivo and in vitro.The AcP-mediated acetylation in K102 inhibits the phosphorylation of PhoP,thus significantly decreasing the activity of PhoP.In turn,the low level of acetylation in K102 is required for the phosphorylation of PhoP and its activity.Therefore,PhoP is acetylated both enzymically and nonenzymically to modulate its activity.The reversible acetylation of PhoP may ensure Salmonella promptly respond to different stresses in host cells,is involved in bacterial virulence across microorganisms.