Metabolic intermediate acetyl phosphate modulates bacterial virulence via acetylation

Abstract

Accumulating evidence indicates that bacterial metabolism plays an important role in virulence. Acetyl phosphate (AcP), the high-energy intermediate of the phosphotransacetylase-acetate kinase pathway, is the major acetyl donor in E. coli . PhoP is an essential transcription factor for bacterial virulence. Here, we show in Salmonella typhimurium that PhoP is non-enzymatically acetylated by AcP, which modifies its transcriptional activity, demonstrating that the acetylation of Lysine 102 (K102) is dependent on the intracellular AcP. The acetylation level of K102 decreases under PhoP-activating conditions including low magnesium, acid stress or following phagocytosis. Notably, in vitro assays show that K102 acetylation affects PhoP phosphorylation and inhibits its transcriptional activity. Both cell and mouse models show that K102 is critical to Salmonella virulence, and suggest acetylation is involved in regulating PhoP activity. Together, the current study highlights the importance of the metabolism in bacterial virulence, and shows AcP might be a key mediator.

A single regulator NrtR controls bacterial NAD+ homeostasis via its acetylation

“…In general, the reversible acetylation of MsNrtR falls into one of two categories: enzymatic action by the acetyltransferase Pat and a non-enzymatic acetyl phosphate (AcP)-dependent m (Figure 6A) (Ren et al, 2016; Ren et al, 2019). Of note, both of these processes can be reversed by the deacetylase CobB (Figure 6A) (Ren et al, 2016; Ren et al, 2019). To address possible origin of K134 acetylation, we integrated an in vitro chemical assay and a genetic exploration in vivo (Figure 6B–I).…”

“…Protein acetylation is a ubiquitous form of post-translational modification in prokaryotes (Ren et al, 2017), which is implicated in central metabolism and even bacterial pathogenicity (Ren et al, 2019; Sang et al, 2016). A global acetylome analysis of M. tuberculosis by Ge and coworkers (Liu et al, 2014) identified almost 137 unique acetylated proteins that are involved in diverse biological processes, some of which had undergone lysine acetylation.…”

Protein Acetylation/Deacetylation: A Potential Strategy for Fungal Infection Control

“…At present, two mechanisms that can regulate acetylation have been identified: one mechanism is mainly regulated by lysine acetyltransferases (KATs), while the other mechanism is non-enzymatic, which can directly introduce lysine residues through the non-enzymatic reaction of acetyl phosphate or acetyl-CoA ( Wagner and Hirschey, 2014 ; Lee et al, 2018 ). In prokaryotes, acetyl phosphate can modulate bacterial virulence through non-enzymatic acetylation ( Ren et al, 2019 ). The main contributor of non-enzymatic acetylation in eukaryotes may be acetyl-CoA in the mitochondria; however, its role still needs to be studied further and is not the focus of this review ( Weinert et al, 2014 ).…”

“…Research on acetylation/deacetylation is currently focused on metabolism, tumor treatment, and other aspects, while there is less research on microbial acetylation, especially regarding microbial virulence. The development of proteomics has resulted in accumulating evidence that protein acetylation/deacetylation is related to microbial virulence and drug resistance ( Hnisz et al, 2010 ; Li et al, 2017 ; Brandão et al, 2018 ; Ren et al, 2019 ). The role of acetylation in regulating bacterial virulence was summarized in a review conducted by Ren et al (2017) .…”

Widespread protein lysine acetylation in gut microbiome and its alterations in patients with Crohn’s disease

“…Compared with other PTMs that are commonly implicated in regulation of metabolic processes, such as phosphorylation, acetylation demonstrated higher levels in microorganisms 10 . In bacteria, up to 40% of proteins can be acetylated 11 , due to the presence of both enzymatic and nonenzymatic acetylation mechanisms [12][13][14][15] . Protein Kac has been characterized in several single bacterial species, including Escherichia coli 13,[16][17][18] , Bacillus subtilis 19 , Salmonella enterica 8 , and Mycobacterium tuberculosis 20 , and widely implicated in various microbial processes, including chemotaxis 21 , nutrient metabolism 18 , stress response 18 , and virulence 22 .…”