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Published Online: 25 September 2015

TrxR1 as a Potent Regulator of the Nrf2-Keap1 Response System

Publication: Antioxidants & Redox Signaling
Volume 23, Issue Number 10


Significance: 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. Recent Advances: 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. Critical Issues: 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. Future Directions: 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. Antioxid. Redox Signal. 23, 823–853.

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Published In

cover image Antioxidants & Redox Signaling
Antioxidants & Redox Signaling
Volume 23Issue Number 10October 1, 2015
Pages: 823 - 853
PubMed: 26058897


Published in print: October 1, 2015
Published online: 25 September 2015
Published ahead of print: 24 June 2015
Published ahead of production: 21 May 2015
Accepted: 20 May 2015
Received: 13 May 2015


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Marcus Cebula
Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
Edward E. Schmidt
Microbiology and Immunology, Montana State University, Bozeman, Montana.
Elias S.J. Arnér
Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.


Address correspondence to:Prof. Elias S.J. ArnérDivision of BiochemistryDepartment of Medical Biochemistry and BiophysicsKarolinska InstitutetStockholm SE-171 77Sweden
E-mail: [email protected]

Author Contributions

M.C., E.E.S., and E.S.J.A. jointly wrote this article, in parts initially based on the PhD thesis of M.C. titled “Intricate aspects of the thioredoxin system in redox signaling” and defended at Karolinska Institutet on May 23, 2014 (

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