NFE2L2 inducers bind to KEAP1:CUL3:RBX1:NFE2L2

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Homo sapiens
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KEAP1:CUL3:RBX1-mediated degradation of NFE2L2 is relieved in the presence of oxidative or electrophilic stress, allowing NFE2L2 to translocate to the nucleus to support expression of target genes. NFE2L2 'inducers' are a varied group of endogenous and extracellular chemicals, including a number of pharmaceutical compounds approved for clinical use (reviewed in Cuadrado, 2019; Baird and Yamamoto, 2020). The mechanism by which NFE2L2:KEAP1 complex senses the oxidative stress and triggers NFE2L2 nuclear localization is unclear. It has been proposed that KEAP1, which is rich in reactive cysteines, may directly sense the oxidative stress via thiol modification and undergo conformational changes that stabilize NFE2L2 (Itoh et al. 1999). The reactive cysteine residues within KEAP1 undergo oxidation and form an intramolecular disulfide bond. Human KEAP1 has 27 cysteine residues and among those C257, C273, C288 and C297 are most reactive and can be oxidized. C273 of one KEAP1 molecule probably forms an intermolecular disulfide bridge with C288 of a second KEAP1 molecule (Zhang & Hannink 2003, Wakabayashi et al. 2004; reviewed in Baird and Yamamoto, 2020). Different NFE2L2 inducers can be grouped on the basis of which KEAP1 cysteine residues are involved in mediating their response (reviewed in Baird and Yamamoto, 2020). NFE2L2 inducers (e.g. sulforaphane, fumarates, and their derivatives) block ubiquitination of NFE2L2 by binding more or less irreversibly to L-cysteine 151 and other cysteine residues of KEAP1 (Brennan et al, 2015; Hu et al, 2011; Unni et al, 2020; Zhu et al, 2019). This strongly enhances induction of expression of all genes with antioxidant response elements (ARE), including HMOX1 and NQO1, among many others (Hong et al, 2005; reviewed in Baird and Yamamoto, 2020).

Sulforaphane has proved to be an effective chemoprotective agent in cell culture, carcinogen-induced and genetic animal cancer models, as well as in xenograft models of cancer (Clarke et al, 2008). These preclinical studies demonstrate chemopreventive mode of actions of isothiocyanates, mainly related to a) detoxification (induction of phase II enzymes), b) anti-inflammatory properties by down-regulation of NFkappaB activity, c) cyclin-mediated cell cycle arrest and d) epigenetic modulation by inhibition of histone deacetylase activity. First prospective clinical trials were promising in patients with risk of prostate cancer recurrence (Gründemann and Huber, 2018; Kamal et al, 2020)

In cancer treatment, sulforaphane exhibited promising inhibitory effects on breast cancer, lung cancer, liver cancer, and other malignant tumors (Wu et al, 2020)

Five clinical trials showed a significant positive correlation between sulforaphane use and autism spectrum disorder (ASD) behavior and cognitive function. The current evidence shows with minimal side effects observed that sulforaphane appears to be a safe and effective treatment option for ASD (McGuinness and Kim, 2020).

Dimethyl fumarate (DMF) was effective in reducing the proportion of patients with MS relapse at 2 years (primary endpoint of DEFINE) and the annualized relapse rate (primary endpoint of CONFIRM) compared with placebo, with reduced disability progression also observed with the drug versus placebo in DEFINE. Dimethyl fumarate also reduced disease activity measures relative to placebo in these trials (Burness and Deeks, 2014; Xu et al, 2015). DMF is completely metabolized to monomethyl fumarate (MMF), and by giving it directly the usually mild side effects are alleviated further (Wynn et al, 2020).

Sulforaphane and dimethyl fumarate show IFN-independent antiviral activity. Both inhibit SARS-CoV-2 replication in vitro. Sulforaphane also inhibits seasonal coronavirus HCoV-OC43 (Olagnier et al, 2020; Ordonez et al, 2021).

Literature References
PubMed ID Title Journal Year
21391649 Modification of keap1 cysteine residues by sulforaphane

Eggler, AL, Hu, C, van Breemen, RB, Mesecar, AD

Chem Res Toxicol 2011
32672401 Structural insights into the multiple binding modes of Dimethyl Fumarate (DMF) and its analogs to the Kelch domain of Keap1

Krishnappa, G, Unni, S, Padmanabhan, B, Kommu, P, Deshmukh, P

FEBS J 2020
16359182 Identification of sensor cysteines in human Keap1 modified by the cancer chemopreventive agent sulforaphane

Hong, F, Liebler, DC, Freeman, ML

Chem Res Toxicol 2005
32284348 The Molecular Mechanisms Regulating the KEAP1-NRF2 Pathway

Yamamoto, M, Baird, L

Mol Cell Biol 2020
33009401 SARS-CoV2-mediated suppression of NRF2-signaling reveals potent antiviral and anti-inflammatory activity of 4-octyl-itaconate and dimethyl fumarate

Nielsen, CG, Hoang, HD, Knudsen, A, van der Horst, D, Holm, CK, Alain, T, Peri, S, Thomsen, M, Lappe, M, Luo, Y, Hansen, AL, Balachandran, S, Idorn, M, Hait, A, Iversen, MB, Svenningsen, EB, Møller, C, Reinert, LS, Hernaez, B, Mogensen, TH, Thyrsted, J, Jørgensen, SE, Bartsch, L, Rehwinkel, J, Huang, J, Ottosen, R, Blay-Cadanet, J, Thielke, AL, Paludan, SR, Hiscott, J, Jakobsen, M, Poulsen, TB, Herengt, A, Schilling, M, Farahani, E, Gilchrist, VH, Olagnier, D, Alcamí, A

Nat Commun 2020
14585973 Distinct cysteine residues in Keap1 are required for Keap1-dependent ubiquitination of Nrf2 and for stabilization of Nrf2 by chemopreventive agents and oxidative stress

Zhang, DD, Hannink, M

Mol. Cell. Biol. 2003
33791708 Sulforaphane exhibits in vitro and in vivo antiviral activity against pandemic SARS-CoV-2 and seasonal HCoV-OC43 coronaviruses

Thompson, EA, Villabona-Rueda, AF, Bullen, CK, Ordonez, AA, Davis, SL, Yolken, RH, Komm, O, Turner, ML, Jones-Brando, L, D'Alessio, FR, Powell, JD, Jain, SK

bioRxiv 2021
14764894 Protection against electrophile and oxidant stress by induction of the phase 2 response: fate of cysteines of the Keap1 sensor modified by inducers

Yamamoto, M, Kang, MI, Kobayashi, A, Wakabayashi, N, Holtzclaw, WD, Talalay, P, Kensler, TW, Dinkova-Kostova, AT

Proc. Natl. Acad. Sci. U.S.A. 2004
25793262 Dimethyl fumarate and monoethyl fumarate exhibit differential effects on KEAP1, NRF2 activation, and glutathione depletion in vitro

Rhodes, KJ, Scannevin, RH, Li, B, Juhasz, P, Matos, MF, Hronowski, X, Gao, B, Brennan, MS

PLoS One 2015
30610225 Therapeutic targeting of the NRF2 and KEAP1 partnership in chronic diseases

Wells, G, Cousin, SP, Franklin, S, Cuadrado, A, Rojo, AI, Hayes, JD, Rumsey, WL, Levonen, AL, Dinkova-Kostova, AT, Kensler, TW, Attucks, OC

Nat Rev Drug Discov 2019
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