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Interplay between cytosolic disulfide reductase systems and the Nrf2/Keap1 pathway

NADPH transfers reducing power from bioenergetic pathways to thioredoxin reductase-1 (TrxR1) and glutathione reductase (GR) to support essential reductive systems. Surprisingly, it was recently shown that mouse livers lacking both TrxR1 and GR (‘TR/GR-null’) can sustain redox (reduction-oxidation) h...

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Autor principal: Schmidt, Edward E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Portland Press Ltd. 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4613508/
https://www.ncbi.nlm.nih.gov/pubmed/26551704
http://dx.doi.org/10.1042/BST20150021
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author Schmidt, Edward E.
author_facet Schmidt, Edward E.
author_sort Schmidt, Edward E.
collection PubMed
description NADPH transfers reducing power from bioenergetic pathways to thioredoxin reductase-1 (TrxR1) and glutathione reductase (GR) to support essential reductive systems. Surprisingly, it was recently shown that mouse livers lacking both TrxR1 and GR (‘TR/GR-null’) can sustain redox (reduction-oxidation) homoeostasis using a previously unrecognized NADPH-independent source of reducing power fuelled by dietary methionine. The NADPH-dependent systems are robustly redundant in liver, such that disruption of either TrxR1 or GR alone does not cause oxidative stress. However, disruption of TrxR1 induces transcription factor Nrf2 (nuclear factor erythroid-derived 2-like-2) whereas disruption of GR does not. This suggests the Nrf2 pathway responds directly to the status of the thioredoxin-1 (Trx1) system. The proximal regulator of Nrf2 is Keap1 (Kelch-like ECH-associated protein-1), a cysteine (Cys)-rich protein that normally interacts transiently with Nrf2, targeting it for degradation. During oxidative stress, this interaction is stabilized, preventing degradation of newly synthesized Nrf2, thereby allowing Nrf2 accumulation. Within the Trx1 system, TrxR1 and peroxiredoxins (Prxs) contain some of the most reactive nucleophilic residues in the cell, making them likely targets for oxidants or electrophiles. We propose that Keap1 activity and therefore Nrf2 is regulated by interactions of Trx1 system enzymes with oxidants. In TR/GR-null livers, Nrf2 activity is further induced, revealing that TrxR-independent systems also repress Nrf2 and these might be induced by more extreme challenges.
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spelling pubmed-46135082015-10-23 Interplay between cytosolic disulfide reductase systems and the Nrf2/Keap1 pathway Schmidt, Edward E. Biochem Soc Trans Biochemical Society Focused Meetings NADPH transfers reducing power from bioenergetic pathways to thioredoxin reductase-1 (TrxR1) and glutathione reductase (GR) to support essential reductive systems. Surprisingly, it was recently shown that mouse livers lacking both TrxR1 and GR (‘TR/GR-null’) can sustain redox (reduction-oxidation) homoeostasis using a previously unrecognized NADPH-independent source of reducing power fuelled by dietary methionine. The NADPH-dependent systems are robustly redundant in liver, such that disruption of either TrxR1 or GR alone does not cause oxidative stress. However, disruption of TrxR1 induces transcription factor Nrf2 (nuclear factor erythroid-derived 2-like-2) whereas disruption of GR does not. This suggests the Nrf2 pathway responds directly to the status of the thioredoxin-1 (Trx1) system. The proximal regulator of Nrf2 is Keap1 (Kelch-like ECH-associated protein-1), a cysteine (Cys)-rich protein that normally interacts transiently with Nrf2, targeting it for degradation. During oxidative stress, this interaction is stabilized, preventing degradation of newly synthesized Nrf2, thereby allowing Nrf2 accumulation. Within the Trx1 system, TrxR1 and peroxiredoxins (Prxs) contain some of the most reactive nucleophilic residues in the cell, making them likely targets for oxidants or electrophiles. We propose that Keap1 activity and therefore Nrf2 is regulated by interactions of Trx1 system enzymes with oxidants. In TR/GR-null livers, Nrf2 activity is further induced, revealing that TrxR-independent systems also repress Nrf2 and these might be induced by more extreme challenges. Portland Press Ltd. 2015-08-03 2015-08-01 /pmc/articles/PMC4613508/ /pubmed/26551704 http://dx.doi.org/10.1042/BST20150021 Text en © 2015 Authors; published by Portland Press Limited
spellingShingle Biochemical Society Focused Meetings
Schmidt, Edward E.
Interplay between cytosolic disulfide reductase systems and the Nrf2/Keap1 pathway
title Interplay between cytosolic disulfide reductase systems and the Nrf2/Keap1 pathway
title_full Interplay between cytosolic disulfide reductase systems and the Nrf2/Keap1 pathway
title_fullStr Interplay between cytosolic disulfide reductase systems and the Nrf2/Keap1 pathway
title_full_unstemmed Interplay between cytosolic disulfide reductase systems and the Nrf2/Keap1 pathway
title_short Interplay between cytosolic disulfide reductase systems and the Nrf2/Keap1 pathway
title_sort interplay between cytosolic disulfide reductase systems and the nrf2/keap1 pathway
topic Biochemical Society Focused Meetings
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4613508/
https://www.ncbi.nlm.nih.gov/pubmed/26551704
http://dx.doi.org/10.1042/BST20150021
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