title: The Oxidative Stress Network of Mycobacterium tuberculosis Reveals Coordination between Radical Detoxification Systems.
abstract: M. tuberculosis (Mtb) survives a hostile environment within the host that is shaped in part by oxidative stress. The mechanisms used by Mtb to resist these stresses remain ill-defined because the complex combination of oxidants generated by host immunity is difficult to accurately recapitulate in vitro. We performed a genome-wide genetic interaction screen to comprehensively delineate oxidative stress resistance pathways necessary for Mtb to resist oxidation during infection. Our analysis predicted functional relationships between the superoxide-detoxifying enzyme (SodA), an integral membrane protein (DoxX), and a predicted thiol-oxidoreductase (SseA). Consistent with that, SodA, DoxX, and SseA form a membrane-associated oxidoreductase complex (MRC) that physically links radical detoxification with cytosolic thiol homeostasis. Loss of any MRC component correlated with defective recycling of mycothiol and accumulation of cellular oxidative damage. This previously uncharacterized coordination between oxygen radical detoxification and thiol homeostasis is required to overcome the oxidative environment Mtb encounters in the host.
authors.affiliation: Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, 55 Lake Avenue N., Worcester, MA 01655, USA.
authors.forename: Subhalaxmi
authors.initials: S
authors.lastname: Nambi
authors.affiliation: Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, 55 Lake Avenue N., Worcester, MA 01655, USA.
authors.forename: Jarukit E
authors.initials: JE
authors.lastname: Long
authors.affiliation: Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, 55 Lake Avenue N., Worcester, MA 01655, USA.
authors.forename: Bibhuti B
authors.initials: BB
authors.lastname: Mishra
authors.affiliation: Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, 55 Lake Avenue N., Worcester, MA 01655, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Baker
authors.affiliation: Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, 55 Lake Avenue N., Worcester, MA 01655, USA.
authors.forename: Kenan C
authors.initials: KC
authors.lastname: Murphy
authors.affiliation: Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, 55 Lake Avenue N., Worcester, MA 01655, USA.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Olive
authors.affiliation: Proteomics and Mass Spectrometry Facility and Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, 55 Lake Avenue N., Worcester, MA 01655 USA.
authors.forename: Hien P
authors.initials: HP
authors.lastname: Nguyen
authors.affiliation: Proteomics and Mass Spectrometry Facility and Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, 55 Lake Avenue N., Worcester, MA 01655 USA.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Shaffer
authors.affiliation: Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, 55 Lake Avenue N., Worcester, MA 01655, USA; Howard Hughes Medical Institute, 4000 Jones Bridge Road, Chevy Chase, MD 20815, USA. Electronic address: christopher.sassetti@umassmed.edu.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Sassetti
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D015964:Gene Expression Regulation, Bacterial; D054884:Host-Pathogen Interactions; D008264:Macrophages / Q000382:microbiology; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009154:Mutation; D009169:Mycobacterium tuberculosis / Q000235:genetics / Q000378:metabolism* / Q000472:pathogenicity; D018384:Oxidative Stress / Q000235:genetics*; D010088:Oxidoreductases / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D013438:Sulfhydryl Compounds / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D014376:Tuberculosis / Q000382:microbiology
chemical_list: D001426:Bacterial Proteins; D017382:Reactive Oxygen Species; D013438:Sulfhydryl Compounds; D010088:Oxidoreductases; C095500:SodA protein, Bacteria; D013482:Superoxide Dismutase