Kelch-like ECH-associated protein 1

Definition:

Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin ligase complex that regulates the response to oxidative stress by targeting NFE2L2/NRF2 for ubiquitination. KEAP1 acts as a key sensor of oxidative and electrophilic stress: in normal conditions, the BCR(KEAP1) complex mediates ubiquitination and degradation of NFE2L2/NRF2, a transcription factor regulating expression of many cytoprotective genes. In response to oxidative stress, different electrophile metabolites trigger non-enzymatic covalent modifications of highly reactive cysteine residues in KEAP1, leading to inactivate the ubiquitin ligase activity of the BCR(KEAP1) complex, promoting NFE2L2/NRF2 nuclear accumulation and expression of phase II detoxifying enzymes. In response to selective autophagy, KEAP1 is sequestered in inclusion bodies following its interaction with SQSTM1/p62, leading to inactivation of the BCR(KEAP1) complex and activation of NFE2L2/NRF2. The BCR(KEAP1) complex also mediates ubiquitination of SQSTM1/p62, increasing SQSTM1/p62 sequestering activity and degradation. The BCR(KEAP1) complex also targets BPTF and PGAM5 for ubiquitination and degradation by the proteasome.

References:

[1]. YouJin Lee, et al. Keap1/Cullin3 Modulates p62/SQSTM1 Activity via UBA Domain Ubiquitination. Cell Rep. 2017 Apr 4;19(1):188-202. [Content Brief]

[2]. Evanna L Mills, et al. Itaconate is an anti-inflammatory metabolite that activates Nrf2 via alkylation of KEAP1. Nature. 2018 Apr 5;556(7699):113-117. [Content Brief]

[3]. Donna D Zhang, et al. Keap1 is a redox-regulated substrate adaptor protein for a Cul3-dependent ubiquitin ligase complex. Mol Cell Biol. 2004 Dec;24(24):10941-53. [Content Brief]

[4]. Gordon D Strachan, et al. Fetal Alz-50 clone 1 interacts with the human orthologue of the Kelch-like Ech-associated protein. Biochemistry. 2004 Sep 28;43(38):12113-22. [Content Brief]

[5]. Ling Gao, et al. Novel n-3 fatty acid oxidation products activate Nrf2 by destabilizing the association between Keap1 and Cullin3. J Biol Chem. 2007 Jan 26;282(4):2529-37. [Content Brief]

[6]. Girish Rachakonda, et al. Covalent modification at Cys151 dissociates the electrophile sensor Keap1 from the ubiquitin ligase CUL3. Chem Res Toxicol. 2008 Mar;21(3):705-10. [Content Brief]

[7]. Manabu Furukawa, et al. BTB protein Keap1 targets antioxidant transcription factor Nrf2 for ubiquitination by the Cullin 3-Roc1 ligase. Mol Cell Biol. 2005 Jan;25(1):162-71. [Content Brief]

[8]. Shih-Ching Lo, et al. PGAM5, a Bcl-XL-interacting protein, is a novel substrate for the redox-regulated Keap1-dependent ubiquitin ligase complex. J Biol Chem. 2006 Dec 8;281(49):37893-903. [Content Brief]

[9]. Donna D Zhang, et al. Ubiquitination of Keap1, a BTB-Kelch substrate adaptor protein for Cul3, targets Keap1 for degradation by a proteasome-independent pathway. J Biol Chem. 2005 Aug 26;280(34):30091-9. [Content Brief]

[10]. Aimee L Eggler, et al. Cul3-mediated Nrf2 ubiquitination and antioxidant response element (ARE) activation are dependent on the partial molar volume at position 151 of Keap1. Biochem J. 2009 Jul 29;422(1):171-80. [Content Brief]

[11]. Aimee L Eggler, et al. Modifying specific cysteines of the electrophile-sensing human Keap1 protein is insufficient to disrupt binding to the Nrf2 domain Neh2. Proc Natl Acad Sci U S A. 2005 Jul 19;102(29):10070-5. [Content Brief]

[12]. Ashish Jain, et al. p62/SQSTM1 is a target gene for transcription factor NRF2 and creates a positive feedback loop by inducing antioxidant response element-driven gene transcription. J Biol Chem. 2010 Jul 16;285(29):22576-91. [Content Brief]

[13]. Donna D Zhang, et al. Distinct cysteine residues in Keap1 are required for Keap1-dependent ubiquitination of Nrf2 and for stabilization of Nrf2 by chemopreventive agents and oxidative stress. Mol Cell Biol. 2003 Nov;23(22):8137-51. [Content Brief]

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