The KEAP1-NRF2 System: a Thiol-Based Sensor-Effector Apparatus for Maintaining Redox Homeostasis

Yamamoto, Masayuki; Kensler, Thomas W.; Motohashi, Hozumi

doi:10.1152/physrev.00023.2017

Cited by 1,320 publications

(1,176 citation statements)

References 270 publications

(323 reference statements)

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“…Under quiescent conditions, Nrf2 is sequestered by Kelch‐like ECH‐associated protein 1 (Keap1) in the cytoplasm for proteasomal degradation. Upon exposure to endogenous or environmental stimuli, Nrf2 is dissociated from Keap1 and then translocated to the nucleus to trigger an anti‐inflammatory program . The alkylation is an important form of protein modification.…”

Section: Activation Of Nrf2mentioning

confidence: 99%

Itaconate: an emerging determinant of inflammation in activated macrophages

Zhang

Zheng

et al. 2018

Immunol Cell Biol

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Macrophages play a central role in innate immunity as the first line of defense against pathogen infection. Upon exposure to inflammatory stimuli, macrophages rapidly respond and subsequently undergo metabolic reprogramming to substantially produce cellular metabolites such as itaconate. As a derivate of the tricarboxylic acid cycle, itaconate is derived from the decarboxylation of cis‐aconitate mediated by immunoresponsive gene 1 in the mitochondrial matrix. It is well known that itaconate has a direct antimicrobial effect by inhibiting isocitrate lyase. Strikingly, two recent studies published in Nature showed that itaconate markedly decreases the production of proinflammatory mediators in lipopolysaccharide‐treated macrophages and ameliorates sepsis and psoriasis in animal models, revealing a novel biological action of itaconate beyond its regular roles in antimicrobial defense. The mechanism for this anti‐inflammatory effect has been proposed to involve the inhibition of succinate dehydrogenase, blockade of IκBζ translation and activation of Nrf2. These intriguing discoveries provide a new explanation for how macrophages are switched from a pro‐ to an anti‐inflammatory state to limit the damage and facilitate tissue repair under proinflammatory conditions. Thus, the emerging effect of itaconate as a crucial determinant of macrophage inflammation has important implications in further understanding cellular immunometabolism and developing future therapeutics for the treatment of inflammatory diseases. In this review, we focus on the roles of itaconate in controlling the inflammatory response during macrophage activation, providing a rationale for future investigation and therapeutic intervention.

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Section: Activation Of Nrf2mentioning

confidence: 99%

Itaconate: an emerging determinant of inflammation in activated macrophages

Zhang

Zheng

et al. 2018

Immunol Cell Biol

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“…Among them, Keap1‐Nrf2/ARE pathway, consists of three parts: Kelch‐like ECH‐associating protein 1 (Keap1), nuclear factor erythroid 2 related factor 2 (Nrf2), and antioxidant responsive element (ARE) cis ‐acting element, is a powerful oxidation‐reduction system and is also an isobiotic sensitive signaling pathway which protects cells from injury and death . In the absence of stress, Keap1 is an E3 ubiquitin ligase substrate adaptor that targets Nrf2 for rapid proteasomal degradation, which results in a limited cytoplasmic concentration of Nrf2 . When exposed to electrophiles or oxidative stress, several highly reactive cysteine residues of Keap1 are modified to prevent it from targeting Nrf2 for proteasome degradation, resulting in rapid accumulation of Nrf2 protein and dimerization with small musculoaponeurotic fibrosarcoma (sMaf) protein.…”

Section: Introductionmentioning

confidence: 99%

Recent Advances of Natural Polyphenols Activators for Keap1‐Nrf2 Signaling Pathway

Zhou

Jiang

et al. 2019

Chemistry & Biodiversity

148

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The Keap1‐Nrf2/ARE signaling pathway is an important defense system against exogenous and endogenous oxidative stress injury. The dysregulation of the signaling pathway is associated with many diseases, such as cancer, diabetes, and respiratory diseases. Over the years, a wide range of natural products has provided sufficient resources for the discovery of potential therapeutic drugs. Among them, polyphenols possess Nrf2 activation, not only inhibit the production of ROS, inhibit Keap1‐Nrf2 protein–protein interaction, but also degrade Keap1 and regulate the Nrf2 related pathway. In fact, with the continuous improvement of natural polyphenols separation and purification technology and further studies on the Keap1‐Nrf2 molecular mechanism, more and more natural polyphenols monomer components of Nrf2 activators have been gradually discovered. In this view, we summarize the research status of natural polyphenols that have been found with apparent Nrf2 activation and their action modes. On the whole, this review may guide the design of novel Keap1‐Nrf2 activator.

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“…4 The antioxidant response is principally mediated by the transcription factor Nrf2, which induces the transcriptional activation of several genes involved in glutathione (GSH) synthesis, chemoresistance and cytoprotection. 4 The antioxidant response is principally mediated by the transcription factor Nrf2, which induces the transcriptional activation of several genes involved in glutathione (GSH) synthesis, chemoresistance and cytoprotection.…”

mentioning

confidence: 99%

Nrf2 promotes breast cancer cell migration via up‐regulation of G6PD/HIF‐1α/Notch1 axis

Zhang

et al. 2019

J Cellular Molecular Medi

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Abnormal metabolism of tumour cells is closely related to the occurrence and development of breast cancer, during which the expression of NF‐E2‐related factor 2 (Nrf2) is of great significance. Metastatic breast cancer is one of the most common causes of cancer death worldwide; however, the molecular mechanism underlying breast cancer metastasis remains unknown. In this study, we found that the overexpression of Nrf2 promoted proliferation and migration of breast cancers cells. Inhibition of Nrf2 and overexpression of Kelch‐like ECH‐associated protein 1 (Keap1) reduced the expression of glucose‐6‐phosphate dehydrogenase (G6PD) and transketolase of pentose phosphate pathway, and overexpression of Nrf2 and knockdown of Keap1 had opposite effects. Our results further showed that the overexpression of Nrf2 promoted the expression of G6PD and Hypoxia‐inducing factor 1α (HIF‐1α) in MCF‐7 and MDA‐MB‐231 cells. Overexpression of Nrf2 up‐regulated the expression of Notch1 via G6PD/HIF‐1α pathway. Notch signalling pathway affected the proliferation of breast cancer by affecting its downstream gene HES‐1, and regulated the migration of breast cancer cells by affecting the expression of EMT pathway. The results suggest that Nrf2 is a potential molecular target for the treatment of breast cancer and targeting Notch1 signalling pathway may provide a promising strategy for the treatment of Nrf2‐driven breast cancer metastasis.

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The KEAP1-NRF2 System: a Thiol-Based Sensor-Effector Apparatus for Maintaining Redox Homeostasis

Cited by 1,320 publications

References 270 publications

Itaconate: an emerging determinant of inflammation in activated macrophages

Itaconate: an emerging determinant of inflammation in activated macrophages

Recent Advances of Natural Polyphenols Activators for Keap1‐Nrf2 Signaling Pathway

Nrf2 promotes breast cancer cell migration via up‐regulation of G6PD/HIF‐1α/Notch1 axis

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