Format

Send to

Choose Destination

See 1 citation found by title matching your search:

Nat Chem Biol. 2020 Jan;16(1):95-103. doi: 10.1038/s41589-019-0392-5. Epub 2019 Nov 18.

Site-specific acylation of a bacterial virulence regulator attenuates infection.

Author information

1
Laboratory of Chemical Biology and Microbial Pathogenesis, The Rockefeller University, New York, NY, USA.
2
Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID), Department of Medicine, University of Cambridge, Cambridge, UK.
3
State Key Laboratory of Chemical Oncogenomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, China.
4
Laboratory of Chemical Biology and Microbial Pathogenesis, The Rockefeller University, New York, NY, USA. hhang@rockefeller.edu.

Abstract

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.

PMID:
31740807
DOI:
10.1038/s41589-019-0392-5

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for Rockefeller University Rita and Frits Markus Library
Loading ...
Support Center