Glutathione activates virulence gene expression of an intracellular pathogen
Open accessAbstract
Intracellular pathogens are responsible for much of the world-wide morbidity and mortality due to infectious diseases. To colonize their hosts successfully, pathogens must sense their environment and regulate virulence gene expression appropriately. Accordingly, on entry into mammalian cells, the facultative intracellular bacterial pathogen Listeria monocytogenes remodels its transcriptional program by activating the master virulence regulator PrfA. Here we show that bacterial and host-derived glutathione are required to activate PrfA. In this study a genetic selection led to the identification of a bacterial mutant in glutathione synthase that exhibited reduced virulence gene expression and was attenuated 150-fold in mice. Genome sequencing of suppressor mutants that arose spontaneously in vivo revealed a single nucleotide change in prfA that locks the protein in the active conformation (PrfA*) and completely bypassed the requirement for glutathione during infection. Biochemical and genetic studies support a model in which glutathione-dependent PrfA activation is mediated by allosteric binding of glutathione to PrfA. Whereas glutathione and other low-molecular-weight thiols have important roles in redox homeostasis in all forms of life, here we demonstrate that glutathione represents a critical signalling molecule that activates the virulence of an intracellular pathogen.
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Bacteria regulate the expression of antioxidant defense networks.
“Bacteria regulate the expression of antioxidant defense networks [190].”
From The Role of Reactive Species on Innate Immunity (2022) · cites this paper as [190]
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References 37 · Cited by 277
- Authors
- Reniere, M. L., Whiteley, A. T., Hamilton, K. L., John, S. M., Lauer, P., Brennan, R. G., & Portnoy, D. A.
- Affiliations
- University of California, Berkeley (US)
- Duke University (US)
- Aduro BioTech (United States) (US)
- Corresponding author
- Portnoy, Daniel A.
- Venue
- Nature
- Published
- 2015-01
- Volume
- 517
- Issue
- 7533
- Pages
- 170-173
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC4305340
- OpenAlex
- W1966612320
- Cited by
- 277
- References
- 37
- Citations by year
- 2026: 18 · 2025: 19 · 2024: 31 · 2023: 20 · 2022: 22 · 2021: 19 · 2020: 28 · 2019: 22 · 2018: 28 · 2017: 38 · 2016: 19 · 2015: 13
- FWCI
- 22.32
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Science Foundation
- University of California Berkeley
- National Institutes of Health
- University of California, San Francisco
- National Institute of General Medical Sciences (T32GM008487, F32GM008487)
- National Institute of Allergy and Infectious Diseases (F32AI104247, 1P01AI63302, 1 R01 AI27655, P01AI063302, R01AI027655)
- National Center for Research Resources (S10RR029668, S10RR027303)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biotechnology › Listeria monocytogenes in Food Safety
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Keywords
- glutathione, Listeria monocytogenes, PrfA, virulence gene expression, allosteric regulation, glutathione synthetase, intracellular pathogens, bacterial virulence regulation
- MeSH terms
- Allosteric Regulation, Bacterial Proteins, DNA, Glutathione, Listeria monocytogenes, Macrophages, Mutation, Peptide Termination Factors, Protein Binding, Selection, Genetic, Suppression, Genetic, Virulence, Gene Expression Regulation, Bacterial, Intracellular Space
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