Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Oxidative Stress-Induced Misfolding and Inclusion Formation of Nrf2 and Keap1

Version 1 : Received: 7 December 2021 / Approved: 9 December 2021 / Online: 9 December 2021 (15:46:41 CET)

A peer-reviewed article of this Preprint also exists.

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. 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.

Journal reference: Antioxidants 2022, 11, 243
DOI: 10.3390/antiox11020243

Abstract

Cells that experience high levels of oxidative stress respond with the induction of antioxidant proteins through the activation of the transcription factor Nrf2. Nrf2 is negatively regulated by Keap1 which binds to Nrf2 to facilitate its ubiquitination and ensuing proteasomal degradation under basal conditions. Here, we study 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 dysregulation by oxidation-induced protein misfolding.

Keywords

Nrf2; Keap1; oxidation; oxidative stress; protein misfolding

Subject

BIOLOGY, Physiology

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