title: TrxR1 as a potent regulator of the Nrf2-Keap1 response system.
abstract: CONCLUSIONS
  All cells must maintain a balance between oxidants and reductants, while allowing for fluctuations in redox states triggered by signaling, altered metabolic flow, or extracellular stimuli. Furthermore, they must be able to rapidly sense and react to various challenges that would disrupt the redox homeostasis.
  
  
  BACKGROUND
  Many studies have identified Keap1 as a key sensor for oxidative or electrophilic stress, with modification of Keap1 by oxidation or electrophiles triggering Nrf2-mediated transcriptional induction of enzymes supporting reductive and detoxification pathways. However, additional mechanisms for Nrf2 regulation are likely to exist upstream of, or in parallel with, Keap1.
  
  
  RESULTS
  Here, we propose that the mammalian selenoprotein thioredoxin reductase 1 (TrxR1) is a potent regulator of Nrf2. A high chemical reactivity of TrxR1 and its vital role for the thioredoxin (Trx) system distinguishes TrxR1 as a prime target for electrophilic challenges. Chemical modification of the selenocysteine (Sec) in TrxR1 by electrophiles leads to rapid inhibition of thioredoxin disulfide reductase activity, often combined with induction of NADPH oxidase activity of the derivatized enzyme, thereby affecting many downstream redox pathways. The notion of TrxR1 as a regulator of Nrf2 is supported by many publications on effects in human cells of selenium deficiency, oxidative stress or electrophile exposure, as well as the phenotypes of genetic mouse models.
  
  
  CONCLUSIONS
  Investigation of the role of TrxR1 as a regulator of Nrf2 activation will facilitate further studies of redox control in diverse cells and tissues of mammals, and possibly also in animals of other classes.
authors.affiliation: 1 Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet , Stockholm, Sweden .
authors.forename: Marcus
authors.initials: M
authors.lastname: Cebula
authors.affiliation: 2 Microbiology and Immunology, Montana State University , Bozeman, Montana.
authors.forename: Edward E
authors.initials: EE
authors.lastname: Schmidt
authors.affiliation: 1 Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet , Stockholm, Sweden .
authors.forename: Elias S J
authors.initials: ES
authors.lastname: Arnér
mesh_terms: D000818:Animals; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D010084:Oxidation-Reduction; D017279:Selenocysteine / Q000378:metabolism; D015398:Signal Transduction; D054481:Thioredoxin Reductase 1 / Q000737:chemistry / Q000378:metabolism*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C431364:KEAP1 protein, human; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D017279:Selenocysteine; D054481:Thioredoxin Reductase 1