Site-specific acylation of a bacterial virulence regulator attenuates infection

• Published in: Nature chemical biology Vol. 16; no. 1; pp. 95 - 103
• Main Authors: Zhang, Zhenrun J., Pedicord, Virginia A., Peng, Tao, Hang, Howard C.
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.01.2020; Nature Publishing Group
• Subjects: 631/326/41; 631/92; 631/92/458; 692/699/255; Acylation; Amino acids; Animals; Arginine - chemistry; Bacterial Proteins - metabolism; Binding Sites; Biochemical Engineering; Biochemistry; Bioorganic Chemistry; Butyrates - chemistry; Carbon sources; Cell Biology; Chemistry; Chemistry and Materials Science; Chemistry/Food Science; CRISPR-Cas Systems; Epithelial cells; Fatty Acids - metabolism; Gene Expression Regulation, Bacterial; Genome editing; Genome, Bacterial; Genomic Islands; Genomics; Lysine - chemistry; Metabolites; Mice; Mice, Inbred C57BL; Microbiota; Mutagenesis; Mutation; Pathogens; Proteomics - methods; Salmonella; Salmonella typhimurium - metabolism; Salmonella typhimurium - pathogenicity; Trans-Activators - metabolism; Transcription; Virulence; Virulence Factors - metabolism
• ISSN: 1552-4450; 1552-4469
• DOI: 10.1038/s41589-019-0392-5

Microbiota generates millimolar concentrations of short-chain fatty acids (SCFAs) that can modulate host metabolism, immunity and susceptibility to infection. Butyrate in particular can function as a carbon source and anti-inflammatory metabolite, but the mechanism by which it inhibits pathogen virulence has been elusive. Using chemical proteomics, we found that several virulence factors encoded by Salmonella pathogenicity island-1 (SPI-1) are acylated by SCFAs. Notably, a transcriptional regulator of SPI-1, HilA, was acylated on several key lysine residues. Subsequent incorporation of stable butyryl-lysine analogs using CRISPR–Cas9 gene editing and unnatural amino acid mutagenesis revealed that site-specific modification of HilA impacts its genomic occupancy, expression of SPI-1 genes and attenuates Salmonella enterica serovar Typhimurium invasion of epithelial cells, as well as dissemination in vivo. Moreover, a multiple-site HilA lysine acylation mutant strain of S . Typhimurium was resistant to butyrate inhibition ex vivo and microbiota attenuation in vivo. Our results suggest that prominent microbiota-derived metabolites may directly acylate virulence factors to inhibit microbial pathogenesis in vivo. Microbiota-derived butyrate acylation of the key Salmonella enterica transcriptional regulator HilA attenuates virulence of the bacteria, blocking invasion of epithelial cells in vitro and dissemination in vivo.