Oxidative Stress-Induced Misfolding and Inclusion Formation of Nrf2 and Keap1
1
Department of Pathology and Laboratory Medicine, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON N6A 3K7, Canada
2
Department of Biochemistry, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON N6A 3K7, Canada
3
Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON N6A 3K7, Canada
*
Author to whom correspondence should be addressed.
Academic Editors: John C. Voss and Young-Sam Keum
Antioxidants 2022, 11(2), 243; https://doi.org/10.3390/antiox11020243
Received: 2 December 2021
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Revised: 24 January 2022
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Accepted: 24 January 2022
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Published: 27 January 2022
(This article belongs to the Special Issue Transcription Factor Nrf2)
Cells that experience high levels of oxidative stress respond by inducing antioxidant proteins through activation of the protein transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2). Nrf2 is negatively regulated by the E3 ubiquitin ligase Kelch-like ECH-associated protein 1 (Keap1), which binds to Nrf2 to facilitate its ubiquitination and ensuing proteasomal degradation under basal conditions. Here, we studied protein folding and misfolding in Nrf2 and Keap1 in yeast, mammalian cells, and purified proteins under oxidative stress conditions. Both Nrf2 and Keap1 are susceptible to protein misfolding and inclusion formation upon oxidative stress. We propose that the intrinsically disordered regions within Nrf2 and the high cysteine content of Keap1 contribute to their oxidation and the ensuing misfolding. Our work reveals previously unexplored aspects of Nrf2 and Keap1 regulation and/or dysregulation by oxidation-induced protein misfolding.
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Keywords:
Nrf2; Keap1; oxidation; oxidative stress; protein misfolding
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MDPI and ACS Style
Ngo, V.; Karunatilleke, N.C.; Brickenden, A.; Choy, W.-Y.; Duennwald, M.L. Oxidative Stress-Induced Misfolding and Inclusion Formation of Nrf2 and Keap1. Antioxidants 2022, 11, 243. https://doi.org/10.3390/antiox11020243
AMA Style
Ngo V, Karunatilleke NC, Brickenden A, Choy W-Y, Duennwald ML. Oxidative Stress-Induced Misfolding and Inclusion Formation of Nrf2 and Keap1. Antioxidants. 2022; 11(2):243. https://doi.org/10.3390/antiox11020243
Chicago/Turabian StyleNgo, Vy, Nadun C. Karunatilleke, Anne Brickenden, Wing-Yiu Choy, and Martin L. Duennwald. 2022. "Oxidative Stress-Induced Misfolding and Inclusion Formation of Nrf2 and Keap1" Antioxidants 11, no. 2: 243. https://doi.org/10.3390/antiox11020243
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