title: Two-component system cross-regulation integrates Bacillus anthracis response to heme and cell envelope stress.
abstract: Two-component signaling systems (TCSs) are one of the mechanisms that bacteria employ to sense and adapt to changes in the environment. A prototypical TCS functions as a phosphorelay from a membrane-bound sensor histidine kinase (HK) to a cytoplasmic response regulator (RR) that controls target gene expression. Despite significant homology in the signaling domains of HKs and RRs, TCSs are thought to typically function as linear systems with little to no cross-talk between non-cognate HK-RR pairs. Here we have identified several cell envelope acting compounds that stimulate a previously uncharacterized Bacillus anthracis TCS. Furthermore, this TCS cross-signals with the heme sensing TCS HssRS; therefore, we have named it HssRS interfacing TCS (HitRS). HssRS reciprocates cross-talk to HitRS, suggesting a link between heme toxicity and cell envelope stress. The signaling between HssRS and HitRS occurs in the parental B. anthracis strain; therefore, we classify HssRS-HitRS interactions as cross-regulation. Cross-talk between HssRS and HitRS occurs at both HK-RR and post-RR signaling junctions. Finally, HitRS also regulates a previously unstudied ABC transporter implicating this transporter in the response to cell envelope stress. This chemical biology approach to probing TCS signaling provides a new model for understanding how bacterial signaling networks are integrated to enable adaptation to complex environments such as those encountered during colonization of the vertebrate host.
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.
authors.forename: Laura A
authors.initials: LA
authors.lastname: Mike
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America; Department of Biology, Grove City College, Grove City, Pennsylvania, United States of America.
authors.forename: Jacob E
authors.initials: JE
authors.lastname: Choby
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America; Department of Biology, Grove City College, Grove City, Pennsylvania, United States of America.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Brinkman
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.
authors.forename: Lorenzo Q
authors.initials: LQ
authors.lastname: Olive
authors.affiliation: Vanderbilt Institute for Chemical Biology, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America.
authors.forename: Brendan F
authors.initials: BF
authors.lastname: Dutter
authors.affiliation: Department of Biology, Grove City College, Grove City, Pennsylvania, United States of America.
authors.forename: Samuel J
authors.initials: SJ
authors.lastname: Ivan
authors.affiliation: Department of Biology, Grove City College, Grove City, Pennsylvania, United States of America.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Gibbs
authors.affiliation: Vanderbilt Institute for Chemical Biology, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America; Department of Chemistry, Vanderbilt University, Nashville, Tennessee, United States of America.
authors.forename: Gary A
authors.initials: GA
authors.lastname: Sulikowski
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America; Department of Biology, Grove City College, Grove City, Pennsylvania, United States of America.
authors.forename: Devin L
authors.initials: DL
authors.lastname: Stauff
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America; Vanderbilt Institute for Chemical Biology, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America.
authors.forename: Eric P
authors.initials: EP
authors.lastname: Skaar
mesh_terms: D001408:Bacillus anthracis / Q000502:physiology*; D001426:Bacterial Proteins / Q000378:metabolism*; D002473:Cell Wall / Q000378:metabolism; D015964:Gene Expression Regulation, Bacterial / Q000502:physiology*; D006418:Heme / Q000378:metabolism*; D026901:Membrane Transport Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D013312:Stress, Physiological
chemical_list: D001426:Bacterial Proteins; D026901:Membrane Transport Proteins; D006418:Heme