Novel bile acid-mediated cysteine modification regulates bacterial virulence
Abstract
Bile acids (BAs) are a class of endogenous metabolites with important roles in fat digestion, vitamin absorption and body signaling. Synthesized from cholesterol in the liver and extensively transformed by the gut microbiota, BAs undergo enterohepatic circulation that places them at a key interface of host–microbe interactions. Current research has focused exclusively on how bile acids interact with the key protein targets in the host and bacteria to transduce signals, however, their potential of forming post-translational modifications (PTMs) in proteomes remains entirely unexplored. We herein report the discovery of a novel cysteine PTM mediated by lithocholic acid (LCA) that is highly conserved across diverse bacterial species. Structural characterization using a series of LCA analogue probes revealed that this modification is formed selectively through C6 of the steroid ring. Functionally, LCA modification disrupts the early stage of Salmonella infection by suppressing its virulence effector SipA and targeting the bacterial protein translocation system. Collectively, our study unveils a previously unrecognized covalent mechanism of BA-mediated regulation, which will open a new venue for exploring the host-microbe interaction and co-metabolism as well as related disorders.
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