Hydrogen Sulfide Sensing through Reactive Sulfur Species (RSS) and Nitroxyl (HNO) in Enterococcus faecalis

Jiangchuan Shen, Brenna J.C. Walsh, Ana Lidia Flores-Mireles, Hui Peng, Yifan Zhang, Yixiang Zhang, Jonathan C. Trinidad, Scott J. Hultgren, David P. Giedroc

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8 Scopus citations


Recent studies of hydrogen sulfide (H 2 S) signaling implicate low molecular weight (LMW) thiol persulfides and other reactive sulfur species (RSS) as signaling effectors. Here, we show that a CstR protein from the human pathogen Enterococcus faecalis (E. faecalis), previously identified in Staphylococcus aureus (S. aureus), is an RSS-sensing repressor that transcriptionally regulates a cst-like operon in response to both exogenous sulfide stress and Angeli's salt, a precursor of nitroxyl (HNO). E. faecalis CstR reacts with coenzyme A persulfide (CoASSH) to form interprotomer disulfide and trisulfide bridges between C32 and C61′, which negatively regulate DNA binding to a consensus CstR DNA operator. A δcstR strain exhibits deficiency in catheter colonization in a catheter-associated urinary tract infection (CAUTI) mouse model, suggesting sulfide regulation and homeostasis is critical for pathogenicity. Cellular polysulfide metabolite profiling of sodium sulfide-stressed E. faecalis confirms an increase in both inorganic polysulfides and LMW thiols and persulfides sensed by CstR. The cst-like operon encodes two authentic thiosulfate sulfurtransferases and an enzyme we characterize here as an NADH and FAD-dependent coenzyme A (CoA) persulfide reductase (CoAPR) that harbors an N-terminal CoA disulfide reductase (CDR) domain and a C-terminal rhodanese homology domain (RHD). Both cysteines in the CDR (C42) and RHD (C508) domains are required for CoAPR activity and complementation of a sulfide-induced growth phenotype of a S. aureus strain lacking cstB, encoding a nonheme Fe II persulfide dioxygenase. We propose that S. aureus CstB and E. faecalis CoAPR employ orthogonal chemistries to lower CoASSH that accumulates under conditions of cellular sulfide toxicity and signaling.

Original languageEnglish
Pages (from-to)1610-1620
Number of pages11
JournalACS Chemical Biology
Issue number6
StatePublished - Jun 15 2018

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    Shen, J., Walsh, B. J. C., Flores-Mireles, A. L., Peng, H., Zhang, Y., Zhang, Y., Trinidad, J. C., Hultgren, S. J., & Giedroc, D. P. (2018). Hydrogen Sulfide Sensing through Reactive Sulfur Species (RSS) and Nitroxyl (HNO) in Enterococcus faecalis. ACS Chemical Biology, 13(6), 1610-1620. https://doi.org/10.1021/acschembio.8b00230