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Review
. 2020 Sep:157:63-74.
doi: 10.1016/j.freeradbiomed.2020.03.023. Epub 2020 Mar 28.

Beyond repression of Nrf2: An update on Keap1

Aleksandra Kopacz  1 , Damian Kloska  1 , Henry Jay Forman  2 , Alicja Jozkowicz  1 , Anna Grochot-Przeczek  3
Affiliations
Review

Beyond repression of Nrf2: An update on Keap1

Aleksandra Kopacz et al. Free Radic Biol Med. 2020 Sep.

Abstract

Nrf2 (NFE2L2 - nuclear factor (erythroid-derived 2)-like 2) is a transcription factor, which is repressed by interaction with a redox-sensitive protein Keap1 (Kelch-like ECH-associated protein 1). Deregulation of Nrf2 transcriptional activity has been described in the pathogenesis of multiple diseases, and the Nrf2/Keap1 axis has emerged as a crucial modulator of cellular homeostasis. Whereas the significance of Nrf2 in the modulation of biological processes has been well established and broadly discussed in detail, the focus on Keap1 rarely goes beyond the regulation of Nrf2 activity and redox sensing. However, recent studies and scrutinized analysis of available data point to Keap1 as an intriguing and potent regulator of cellular function. This review aims to shed more light on Keap1 structure, interactome, regulation and non-canonical functions, thereby enhancing its significance in cell biology. We also intend to highlight the impact of balance between Keap1 and Nrf2 in the maintenance of cellular homeostasis.

Keywords: Interacting proteins; Keap1; Non-canonical functions; Nrf2.

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Figures

Fig. 1.
Fig. 1.. Keap1 structure.
(A) The organisation of Keap1 domains. NTR – N terminal region. BTB - Broad-Complex, Tramtrack and Bric a brac. IVR- intervening region. DGR - double-glycine repeat region. CTR – C terminal region; (B) Schematic illustration of the Keap1-Cul3-E3 ligase complex interacting with the Neh2 domain of Nrf2 via the DLG and ETGE motifs. Cul3 – cullin3; Rbx1 – RING box protein 1; E2 – Ubiquitin ligase with ubiquitin (yellow circles).
Fig. 2.
Fig. 2.. The modes of Keap1 regulation.
The level and activity of Keap1 are regulated via several mechanisms: transcription factors, epigenetic modifications, miRNAs, somatic mutations, post-translational modifications, and degradation. VA – valproic acid, MGO – methylglyoxal.
Fig. 3.
Fig. 3.. Alignment of the confirmed Keap1 interaction motifs.
See this image and copyright information in PMC

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