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.
SIRT family proteins are highly conserved both in the structure and function among all the organisms, and are involved in gene silencing, DNA damage repair, cell growth and metabolism. Here, a SIRT4 homologue MSMEG_4620 was identified and characterized in Mycobacterium smegmatis. MSMEG_4620 exhibits deacetylase activity that can be activated by fatty acids. Interestingly, MSMEG_4620 also possesses auto ADP-ribosylation activity. MSMEG_4620 is modified on arginine residues as revealed by a chemical stability assay. Moreover, the auto ADP-ribosylation activity of MSMEG_4620 was found to be enhanced by ferric ion. Notably, the SIRT4 homologues are widely distributed in the genomes of environmental mycobacterial species instead of pathogenic mycobacterial species. When MSMEG_4620 was deleted in M. smegmatis, the mutant strain showed a growth defect in 7H9 minimal medium compared with the parental strain. Taken together, these results provided the characteristics of a SIRT4 homologue in prokaryotes and implicated its critical roles in the growth of environmental mycobacterial species.
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