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Secreted transcription factor controls Mycobacterium tuberculosis virulence
Open accessAbstract
Bacterial pathogens trigger specialized virulence factor secretion systems on encountering host cells. The ESX-1 protein secretion system of Mycobacterium tuberculosis-the causative agent of the human disease tuberculosis-delivers bacterial proteins into host cells during infection and is critical for virulence, but how it is regulated is unknown. Here we show that EspR (also known as Rv3849) is a key regulator of ESX-1 that is required for secretion and virulence in mice. EspR activates transcription of an operon that includes three ESX-1 components, Rv3616c-Rv3614c, whose expression in turn promotes secretion of ESX-1 substrates. EspR directly binds to and activates the Rv3616c-Rv3614c promoter and, unexpectedly, is itself secreted from the bacterial cell by the ESX-1 system that it regulates. Efflux of the DNA-binding regulator results in reduced Rv3616c-Rv3614c transcription, and thus reduced ESX-1 secretion. Our results reveal a direct negative feedback loop that regulates the activity of a secretion system essential for virulence. As the virulence factors secreted by the ESX-1 system are highly antigenic, fine control of secretion may be critical to successful infection.
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“Thus far, four ESX-1 substrates have been identified in addition to ESAT-6 and CFP-10. These substrates are called EspA [39], EspB [46], EspR [41], and the M. marinum homologue of Rv3864 [22].”
From Systematic Genetic Nomenclature for Type VII Secretion Systems (2009) · cites this paper as [41]
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Metadata
- Authors
- Raghavan, S., Manzanillo, P., Chan, K., Dovey, C., & Cox, J. S.
- Affiliations
- University of California, San Francisco (US)
- Corresponding author
- Cox, Jeffery S.
- Venue
- Nature
- Published
- 2008-08-07
- Volume
- 454
- Issue
- 7205
- Pages
- 717-721
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC2862998
- OpenAlex
- W1973827044
- Cited by
- 202
- References
- 42
- Citations by year
- 2026: 7 · 2025: 6 · 2024: 4 · 2023: 7 · 2022: 5 · 2021: 5 · 2020: 9 · 2019: 11 · 2018: 6 · 2017: 9 · 2016: 13 · 2015: 14 · 2014: 16 · 2013: 15 · 2012: 19
- FWCI
- 12.06
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- W. M. Keck Foundation
- National Institutes of Health
- National Institute of Allergy and Infectious Diseases (AI63302, AI51667, R01AI051667, P01AI063302)
- Topics
- Health Sciences › Medicine › Infectious Diseases › Tuberculosis Research and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
- Life Sciences › Immunology and Microbiology › Microbiology › Escherichia coli research studies
- Keywords
- Mycobacterium tuberculosis, ESX-1 secretion system, transcriptional regulation, virulence factors, negative feedback loop, promoter activation, tuberculosis vaccine development, host-pathogen interaction
- MeSH terms
- Animals, Bacterial Proteins, Macrophages, Mice, Inbred C57BL, Mycobacterium tuberculosis, Operon, Promoter Regions, Genetic, Transcription Factors, Transcription, Genetic, Virulence, Transcriptional Activation, Gene Expression Regulation, Bacterial, Virulence Factors, Mice
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