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Title: RitR is an archetype for a novel family of redox sensors in the streptococci that has evolved from two-component response regulators and is required for pneumococcal colonization

Abstract

To survive diverse host environments, the human pathogen Streptococcus pneumoniae must prevent its self-produced, extremely high levels of peroxide from reacting with intracellular iron. However, the regulatory mechanism(s) by which the pneumococcus accomplishes this balance remains largely enigmatic, as this pathogen and other related streptococci lack all known redox-sensing transcription factors. Here we describe a two-component-derived response regulator, RitR, as the archetype for a novel family of redox sensors in a subset of streptococcal species. We show that RitR works to both repress iron transport and enable nasopharyngeal colonization through a mechanism that exploits a single cysteine (Cys128) redox switch located within its linker domain. Biochemical experiments and phylogenetics reveal that RitR has diverged from the canonical two-component virulence regulator CovR to instead dimerize and bind DNA only upon Cys128 oxidation in air-rich environments. Atomic structures show that Cys128 oxidation initiates a “helical unravelling” of the RitR linker region, suggesting a mechanism by which the DNA-binding domain is then released to interact with its cognate regulatory DNA. Expanded computational studies indicate this mechanism could be shared by many microbial species outside the streptococcus genus.

Authors:
ORCiD logo [1];  [2]; ORCiD logo [3]; ORCiD logo [4]; ORCiD logo [4]; ORCiD logo [4];  [4];  [5];  [4];  [2]; ORCiD logo [1];  [6]
  1. Loyola Univ. Chicago, Maywood, IL (United States); Imperial College, London (United Kingdom)
  2. Univ. of Wisconsin, Milwaukee, WI (United States)
  3. Univ. of Wisconsin, Madison, WI (United States)
  4. Univ. of Leicester (United Kingdom)
  5. Imperial College, London (United Kingdom)
  6. Univ. of Alabama, Birmingham, AL (United States)
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States)
Sponsoring Org.:
Wellcome Trust and Royal Society; Microbiology Society Harry Smith Vacation Studentship
OSTI Identifier:
1455248
Grant/Contract Number:  
107660/Z/15Z; VS16/73
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
PLoS Pathogens
Additional Journal Information:
Journal Volume: 14; Journal Issue: 5; Journal ID: ISSN 1553-7374
Publisher:
Public Library of Science
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; cysteine; pneumococcus; oxidation; peroxides; transcription factors; dimerization; oxygen; sequence motif analysis

Citation Formats

Glanville, David G., Han, Lanlan, Maule, Andrew F., Woodacre, Alexandra, Thanki, Devsaagar, Abdullah, Iman Tajer, Morrissey, Julie A., Clarke, Thomas B., Yesilkaya, Hasan, Silvaggi, Nicholas R., Ulijasz, Andrew T., and Orihuela, Carlos Javier. RitR is an archetype for a novel family of redox sensors in the streptococci that has evolved from two-component response regulators and is required for pneumococcal colonization. United States: N. p., 2018. Web. doi:10.1371/journal.ppat.1007052.
Glanville, David G., Han, Lanlan, Maule, Andrew F., Woodacre, Alexandra, Thanki, Devsaagar, Abdullah, Iman Tajer, Morrissey, Julie A., Clarke, Thomas B., Yesilkaya, Hasan, Silvaggi, Nicholas R., Ulijasz, Andrew T., & Orihuela, Carlos Javier. RitR is an archetype for a novel family of redox sensors in the streptococci that has evolved from two-component response regulators and is required for pneumococcal colonization. United States. doi:10.1371/journal.ppat.1007052.
Glanville, David G., Han, Lanlan, Maule, Andrew F., Woodacre, Alexandra, Thanki, Devsaagar, Abdullah, Iman Tajer, Morrissey, Julie A., Clarke, Thomas B., Yesilkaya, Hasan, Silvaggi, Nicholas R., Ulijasz, Andrew T., and Orihuela, Carlos Javier. Fri . "RitR is an archetype for a novel family of redox sensors in the streptococci that has evolved from two-component response regulators and is required for pneumococcal colonization". United States. doi:10.1371/journal.ppat.1007052. https://www.osti.gov/servlets/purl/1455248.
@article{osti_1455248,
title = {RitR is an archetype for a novel family of redox sensors in the streptococci that has evolved from two-component response regulators and is required for pneumococcal colonization},
author = {Glanville, David G. and Han, Lanlan and Maule, Andrew F. and Woodacre, Alexandra and Thanki, Devsaagar and Abdullah, Iman Tajer and Morrissey, Julie A. and Clarke, Thomas B. and Yesilkaya, Hasan and Silvaggi, Nicholas R. and Ulijasz, Andrew T. and Orihuela, Carlos Javier},
abstractNote = {To survive diverse host environments, the human pathogen Streptococcus pneumoniae must prevent its self-produced, extremely high levels of peroxide from reacting with intracellular iron. However, the regulatory mechanism(s) by which the pneumococcus accomplishes this balance remains largely enigmatic, as this pathogen and other related streptococci lack all known redox-sensing transcription factors. Here we describe a two-component-derived response regulator, RitR, as the archetype for a novel family of redox sensors in a subset of streptococcal species. We show that RitR works to both repress iron transport and enable nasopharyngeal colonization through a mechanism that exploits a single cysteine (Cys128) redox switch located within its linker domain. Biochemical experiments and phylogenetics reveal that RitR has diverged from the canonical two-component virulence regulator CovR to instead dimerize and bind DNA only upon Cys128 oxidation in air-rich environments. Atomic structures show that Cys128 oxidation initiates a “helical unravelling” of the RitR linker region, suggesting a mechanism by which the DNA-binding domain is then released to interact with its cognate regulatory DNA. Expanded computational studies indicate this mechanism could be shared by many microbial species outside the streptococcus genus.},
doi = {10.1371/journal.ppat.1007052},
journal = {PLoS Pathogens},
issn = {1553-7374},
number = 5,
volume = 14,
place = {United States},
year = {2018},
month = {5}
}

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