Role of human Keap1 S53 and S293 residues in modulating the binding of Keap1 to Nrf2

Sang, Wei; Pei, Yechun; Wang, Yuerong; Guan, Huai; Huang, Yonglin; Xing, Tong; Johnson, Rodney W.; Wang, Dayong

doi:10.1016/j.biochi.2018.12.008

Cited by 10 publications

(8 citation statements)

References 30 publications

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“…However, a recent study has found that the conformational change occurs via the synergy of Cys226, Cys613, and Cys622/Cys624, inactivating Keap1 and stabilizing Nrf2 [52]. In addition, H 2 O 2 mediates Keap1 phosphorylation at Ser 104 , Ser 53 , and Ser 293 in response to oxidative stress [53,54]. Given that different chemicals can target different cysteine sites in Keap1 to regulate Nrf2, chemical Nrf2 inducers have been divided into at least five categories as shown in Figure 2: I (Cys151 preferring), II (Cys288 preferring), III (Cys151/Cys273/Cys288 collaboration preferring), IV (Cys151/Cys273/Cys288 independent), and V (Keap1-Nrf2 protein-protein interaction) [55].…”

Section: Mechanisms Of Nrf2 Dissolution From Keap1mentioning

confidence: 99%

The Keap1-Nrf2 System: A Mediator between Oxidative Stress and Aging

Chao

Xiao

2021

Oxidative Medicine and Cellular Longevity

190

136

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Oxidative stress, a term that describes the imbalance between oxidants and antioxidants, leads to the disruption of redox signals and causes molecular damage. Increased oxidative stress from diverse sources has been implicated in most senescence-related diseases and in aging itself. The Kelch-like ECH-associated protein 1- (Keap1-) nuclear factor-erythroid 2-related factor 2 (Nrf2) system can be used to monitor oxidative stress; Keap1-Nrf2 is closely associated with aging and controls the transcription of multiple antioxidant enzymes. Simultaneously, Keap1-Nrf2 signaling is also modulated by a more complex regulatory network, including phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt), protein kinase C, and mitogen-activated protein kinase. This review presents more information on aging-related molecular mechanisms involving Keap1-Nrf2. Furthermore, we highlight several major signals involved in Nrf2 unbinding from Keap1, including cysteine modification of Keap1 and phosphorylation of Nrf2, PI3K/Akt/glycogen synthase kinase 3β, sequestosome 1, Bach1, and c-Myc. Additionally, we discuss the direct interaction between Keap1-Nrf2 and the mammalian target of rapamycin pathway. In summary, we focus on recent progress in research on the Keap1-Nrf2 system involving oxidative stress and aging, providing an empirical basis for the development of antiaging drugs.

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Section: Mechanisms Of Nrf2 Dissolution From Keap1mentioning

confidence: 99%

The Keap1-Nrf2 System: A Mediator between Oxidative Stress and Aging

Chao

Xiao

2021

Oxidative Medicine and Cellular Longevity

190

136

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“…Moreover, our data confirmed that SpvB restrains the phosphorylation of IKKb through KEAP1. Wei et al recently reported that S53 is a potential phosphorylation site of KEAP1 and its phosphorylation is critical to the activity of KEAP1 (Wei et al, 2019). It is possible that SpvB upregulates the expression of cytosolic KEAP1, and the latter competes with IKKb for phosphate groups in order to maintain its own activity, which leads to the inhibition of NF-kB signaling pathway.…”

Section: Discussionmentioning

confidence: 99%

Salmonella Effector SpvB Inhibits NF-κB Activity via KEAP1-Mediated Downregulation of IKKβ

Yang

Deng

Sun

et al. 2021

Front. Cell. Infect. Microbiol.

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Bacterial pathogens have a broad arsenal of genes that are tightly regulated and coordinated to facilitate adaptation to alter host inflammatory response and prolong intracellular bacterial survival. Salmonella enterica serovar Typhimurium utilizes a type III secretion system (T3SS) to deliver effector molecules into host cells and regulate signal transduction pathways such as NF-κB, thereby resulting in salmonellosis. SpvB, a pSLT-encoded cytotoxic protein secreted by Salmonella pathogenicity island-2 T3SS, is associated with enhanced Salmonella survival and intracellular replication. In this report, we characterized the effects of SpvB on NF-κB signaling pathway. We showed that SpvB has a potent and specific ability to prevent NF-κB activation by targeting IκB kinase β (IKKβ). Previous studies from our laboratory showed that SpvB decreases Nrf2 through its C-terminal domain. Here we further demonstrated that KEAP1, a cytoplasmic protein that interacts with Nrf2 and mediates its proteasomal degradation, is involved in SpvB-induced downregulation of IKKβ expression and phosphorylation. Reduction of KEAP1 by small-interfering RNA prevented the suppression of IKKβ and its phosphorylation mediated by SpvB. These findings revealed a novel mechanism by which Salmonella modulates NF-κB activity to ultimately facilitate intracellular bacterial survival and proliferation and delay host immune response to establish infection.

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“…[ 76 ] The phosphorylation sites in Keap1 such as S53 can respond to oxidative stress and strengthen anti‐oxidation. [ 76 ] With the occurrence of oxidation or covalent modification in Cys273 and Cys288 in the IVR domain, the ubiquitination by Keap1 becomes reduced and the stabilization of Nrf2 is strengthened. [ 77 ] However, the Cys151 in the BTB domain can promote the hypoubiquitination of Nrf2 and the separation of Nrf2 and Keap1.…”

Section: Keap1/nrf2/are Signaling Pathway and Oxidative Stressmentioning

confidence: 99%

“…[ 74,75 ] The phosphorylation of amino acid residues of Keap1 can contribute to the separation between Keap1 and Nrf2. [ 76 ] The phosphorylation sites in Keap1 such as S53 can respond to oxidative stress and strengthen anti‐oxidation. [ 76 ] With the occurrence of oxidation or covalent modification in Cys273 and Cys288 in the IVR domain, the ubiquitination by Keap1 becomes reduced and the stabilization of Nrf2 is strengthened.…”

Section: Keap1/nrf2/are Signaling Pathway and Oxidative Stressmentioning

confidence: 99%

Protective effects of natural compounds against oxidative stress in ischemic diseases and cancers via activating the Nrf2 signaling pathway: A mini review

Sun

et al. 2020

J Biochem & Molecular Tox

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Oxidative stress, an imbalance between reactive oxygen species and antioxidants, has been seen in the pathological states of many disorders such as ischemic diseases and cancers. Many natural compounds (NCs) have long been recognized to ameliorate oxidative stress due to their inherent antioxidant activities. The modulation of oxidative stress by NCs via activating the Nrf2 signaling pathway is summarized in the review. Three NCs, ursolic acid, betulinic acid, and curcumin, and the mechanisms of their cytoprotective effects are investigated in myocardial ischemia, cerebral ischemia, skin cancer, and prostate cancer. To promote the therapeutic performance of NCs with poor water solubility, the formulation approach, such as the nano drug delivery system, is elaborated as well in this review.

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Role of human Keap1 S53 and S293 residues in modulating the binding of Keap1 to Nrf2

Cited by 10 publications

References 30 publications

The Keap1-Nrf2 System: A Mediator between Oxidative Stress and Aging

The Keap1-Nrf2 System: A Mediator between Oxidative Stress and Aging

Salmonella Effector SpvB Inhibits NF-κB Activity via KEAP1-Mediated Downregulation of IKKβ

Protective effects of natural compounds against oxidative stress in ischemic diseases and cancers via activating the Nrf2 signaling pathway: A mini review

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