Suppression of NF-κB signaling by KEAP1 regulation of IKKβ activity through autophagic degradation and inhibition of phosphorylation

Kim, Jeong Eun; You, Dong Joo; Lee, Cheolju; Ahn, Curie; Seong, Jae Young; Hwang, Jong Ik

doi:10.1016/j.cellsig.2010.06.004

Cited by 198 publications

(163 citation statements)

References 32 publications

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“…During this period, Keap1 functions as a CUL3-based E3 ligase of IKKβ and induce IKKβ ubiquitination (33). A similar conclusion was obtained recently by others that Keap1 is involved in the negative regulation of NF-κB signaling through the inhibition of IKKβ phosphorylation and the mediation of autophagy-dependent IKKβ degradation (34). Of interest, this effect of Keap1 on IKKβ was confirmed to exist only in human, chimpanzee, and dog and not in rat or mouse (33).…”

Section: Discussionsupporting

confidence: 55%

“…It is possible that another regulatory mechanisms contribute to the effects of EGCG. Nrf2 is a major target degraded by Keap1, which was also reported to repress NF-κB function by inducing IKKβ degradation (33,34), we questioned whether the NF-κB inhibitive function of EGCG might be related partially to Keap1. Consequently, our results have confirmed the hypothesis.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, these data suggest that the enhancement of nuclear Nrf2 level is probably a major, but not the only, mechanism contributing to the effects of EGCG. Previous studies have reported that Keap1 represses NF-κB function by inducing IKKβ degradation (33,34). Therefore, we tested the function of Keap1 involved in the effects of EGCG.…”

Section: Egcg Prevents Tnf-α-induced Nf-κb Activation and Upregulatesmentioning

confidence: 99%

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Epigallocatechin-3-gallate prevents TNF-α-induced NF-κB activation thereby upregulating ABCA1 via the Nrf2/Keap1 pathway in macrophage foam cells

et al. 2012

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Abstract. The ATP-binding membrane cassette transporter A1 (ABCA1) plays a protective role in the development of atherosclerosis for the reverse cholesterol transport process. Epigallocatechin-3-gallate (EGCG), which exists abundantly in green tea, exerts an anti-atherosclerotic effect via antiinflammatory and metabolic regulation activities. Many genes and proteins related to lipid metabolism are involved in the lowering cholesterol effects of EGCG. However, effects of EGCG on ABCA1 have rarely been described. In the study presented here, we found that exposure of macrophage foam cells to TNF-α results in a downregulation of ABCA1 and a decrease in cholesterol efflux to apoA1, which is attenuated by pretreatment with EGCG. Moreover, rather than activating the Liver X receptor (LXR) pathway, inhibition of the TNF-α-induced nuclear factor-κB (NF-κB) activity is detected with EGCG treatment in cells. In order to inhibit the NF-κB activity, EGCG can promote the dissociation of the nuclear factor E2-related factor 2 (Nrf2)-Kelch-like ECH-associated protein 1 (Keap1) complex; when the released Nrf2 translocates to the nucleus and activates the transcription of genes containing an ARE element inhibition of NF-κB occurs and Keap1 is separated from the complex to directly interact with IKKβ and thus represses NF-κB function. These results provide novel insight into the anti-inflammatory effects of EGCG, as well as the identification of a novel potential therapeutic role for the prevention of atherosclerosis.

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Section: Discussionsupporting

confidence: 55%

Section: Discussionmentioning

confidence: 99%

Section: Egcg Prevents Tnf-α-induced Nf-κb Activation and Upregulatesmentioning

confidence: 99%

See 1 more Smart Citation

Epigallocatechin-3-gallate prevents TNF-α-induced NF-κB activation thereby upregulating ABCA1 via the Nrf2/Keap1 pathway in macrophage foam cells

et al. 2012

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“…Interestingly, IKBKB activity can also be downregulated by autophagic degradation, suggesting a complex interplay between autophagy and the IKK-NFKB pathway. 12,13 In this study, we sought to delineate the intracellular signals necessary to induce autophagy in cells deprived of ECM contact. Whereas the PI3K-AKT-MTORC1 pathway is a major regulator of autophagy induction in detached mouse fibroblasts, the activation of IKK complex plays a key role in promoting autophagy in MECs deprived of ECM contact.…”

Section: Resultsmentioning

confidence: 99%

IκB kinase complex (IKK) triggers detachment-induced autophagy in mammary epithelial cells independently of the PI3K-AKT-MTORC1 pathway

Chen

Debnath

2013

Autophagy

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“…2C) (Rada et al, 2011(Rada et al, , 2012. Moreover, KEAP1 interacts with other proteins that also contain the high-affinity binding motif ETGE (Hast et al, 2013), such as Bcl-2 and IKKb (Kim et al, 2010a;Cazanave et al, 2014). Therefore, some results obtained from KEAP1-deficient cells may not necessarily be related to NRF2 activation.…”

Section: A Electrophilic Nuclear Factor (Erythroid-derived 2)-like 2mentioning

confidence: 98%

Transcription Factor NRF2 as a Therapeutic Target for Chronic Diseases: A Systems Medicine Approach

et al. 2018

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Suppression of NF-κB signaling by KEAP1 regulation of IKKβ activity through autophagic degradation and inhibition of phosphorylation

Cited by 198 publications

References 32 publications

Epigallocatechin-3-gallate prevents TNF-α-induced NF-κB activation thereby upregulating ABCA1 via the Nrf2/Keap1 pathway in macrophage foam cells

Epigallocatechin-3-gallate prevents TNF-α-induced NF-κB activation thereby upregulating ABCA1 via the Nrf2/Keap1 pathway in macrophage foam cells

IκB kinase complex (IKK) triggers detachment-induced autophagy in mammary epithelial cells independently of the PI3K-AKT-MTORC1 pathway

Transcription Factor NRF2 as a Therapeutic Target for Chronic Diseases: A Systems Medicine Approach

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