Cysteine-based regulation of the CUL3 adaptor protein Keap1

Sekhar, Konjeti R.; Rachakonda, Girish; Freeman, Michael L.

doi:10.1016/j.taap.2009.06.016

Cited by 137 publications

(104 citation statements)

References 56 publications

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“…Nrf2 is normally sequestered in the cytoplasm by two proteins, Cul3 and Keap1, that lead to its ubiquitin-mediated degradation. In the setting of oxidative stress, key cysteine residues in Keap1 are oxidized, causing disruption of ubiquitination and accumulation of Nrf2 in both the cytoplasm and the nucleus (48)(49)(50). In islets, we show that total Nrf2 levels are reduced by cytokine incubation and restored upon the deletion of 12-LO.…”

Section: Discussionmentioning

confidence: 76%

12-Lipoxygenase Promotes Obesity-Induced Oxidative Stress in Pancreatic Islets

Tersey

Maier

Nishiki

et al. 2014

Molecular and Cellular Biology

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High-fat diets lead to obesity, inflammation, and dysglycemia. 12-Lipoxygenase (12-LO) is activated by high-fat diets and catalyzes the oxygenation of cellular arachidonic acid to form proinflammatory intermediates. We hypothesized that 12-LO in the pancreatic islet is sufficient to cause dysglycemia in the setting of high-fat feeding. To test this, we generated pancreas-specific 12-LO knockout mice and studied their metabolic and molecular adaptations to high-fat diets. Whereas knockout mice and control littermates displayed identical weight gain, body fat distribution, and macrophage infiltration into fat, knockout mice exhibited greater adaptive islet hyperplasia, improved insulin secretion, and complete protection from dysglycemia. At the molecular level, 12-LO deletion resulted in increases in islet antioxidant enzymes Sod1 and Gpx1 in response to high-fat feeding. The absence or inhibition of 12-LO led to increases in nuclear Nrf2, a transcription factor responsible for activation of genes encoding antioxidant enzymes. Our data reveal a novel pathway in which islet 12-LO suppresses antioxidant enzymes and prevents the adaptive islet responses in the setting of high-fat diets.O besity, typically a result of diets high in saturated fat content, is directly correlated to insulin resistance and prediabetes. Macrovascular disease consequences, including stroke, myocardial infarction, and mortality increase even as blood sugars rise in the prediabetic phase (1), thus emphasizing the perils of glycemic dysregulation in the absence of frank diabetes. High-fat diets (HFDs) and their consequent insulin resistance lead to adaptive islet hyperplasia, in which basal secretion of insulin is increased in an attempt to compensate for insulin resistance (2). However, this compensatory mechanism can eventually fail in the face of prolonged insulin resistance. Inflammation and oxidative stress are major factors thought to contribute to dysfunction of ␤ cells in the setting of insulin resistance (3, 4). In this regard, ␤ cells have low expression and activity levels of the antioxidant enzymes compared to other metabolic tissues (5), and the pathway(s) that endogenously suppresses production of these antioxidant enzymes in the ␤ cell remains unclear.The lipoxygenases represent a group of enzymes that catalyzes the oxygenation of polyunsaturated fatty acids to form inflammatory lipid intermediates, which have been shown to contribute to oxidative stress (6). In the mouse, 12-lipoxygenase (12-LO) is expressed in several cell types, including macrophages, white adipocytes, and pancreatic islets (7). 12-LO oxygenates membranederived arachidonic acid primarily at the 12-position carbon atom to form 12-hydroperoxyeicosatetraenoic acid (12-HPETE), which is then converted to the more stable form 12-hydroxyeicosatetraenoic acid (12-HETE) (7). The role of 12-LO in the setting of HFDs and obesity has been studied primarily in the context of whole-body 12-LO knockout mice. Recent studies showed that 12-LO knockout mice fed a HFD exhibit r...

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Section: Discussionmentioning

confidence: 76%

12-Lipoxygenase Promotes Obesity-Induced Oxidative Stress in Pancreatic Islets

Tersey

Maier

Nishiki

et al. 2014

Molecular and Cellular Biology

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“…Upon stimulation of cells with reactive oxygen species, the reactive cysteine residues undergo oxidation and form an intramolecular disulfide bond (38,39). It is generally accepted that the modification of critical cysteines Cys257, Cys273, and Cys288 causes a conformational change of Keap1 and leads to the release of Nrf2 from Keap1 and subsequent Nrf2 nuclear translocation and activation (40,41).…”

Section: Discussionmentioning

confidence: 99%

Toll-Like Receptor Signaling Induces Nrf2 Pathway Activation through p62-Triggered Keap1 Degradation

Yin

Cao

2015

Molecular and Cellular Biology

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Toll-like receptors (TLRs) induce inflammation and tissue repair through multiple signaling pathways. The Nrf2 pathway plays a key role in defending against the tissue damage incurred by microbial infection or inflammation-associated diseases. The critical event that mediates TLR-induced Nrf2 activation is still poorly understood. In this study, we found that lipopolysaccharide (LPS) and other Toll-like receptor (TLR) agonists activate Nrf2 signaling and the activation is due to the reduction of Keap1, the key Nrf2 inhibitor. TLR signaling-induced Keap1 reduction promoted Nrf2 translocation from the cytoplasm to the nucleus, where it activated transcription of its target genes. TLR agonists modulated Keap1 at the protein posttranslation level through autophagy. TLR signaling increased the expression of autophagy protein p62 and LC3-II and induced their association with Keap1 in the autophagosome-like structures. We also characterized the interaction between p62 and Keap1 and found that p62 is indispensable for TLR-mediated Keap1 reduction: TLR signaling had no effect on Keap1 if cells lacked p62 or if cells expressed a mutant Keap1 that could not interact with p62. Our study indicates that p62-mediated Keap1 degradation through autophagy represents a critical linkage for TLR signaling regulation of the major defense network, the Nrf2 signaling pathway.

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“…In view of reports of multiple reactive cysteines, it was proposed that Keap1-Nrf2-Cul3 complex constitutes a multiple-sensing mechanism 80 . The reactivity of Keap1 cysteine residues with various inducers has been reviewed 81 . Although the complete crystal structure of the Keap1-Nrf2-Cul3 complex has not been resolved yet, some individual domains and their interactions have been revealed.…”

Section: Keap1-dependent Regulation Of Nrf2mentioning

confidence: 99%

The role of modulation of antioxidant enzyme systems in the treatment of neurodegenerative diseases

Obuobi

Karatayev

Chai

et al. 2016

Journal of Enzyme Inhibition and Medicinal Chemistry

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Oxidative stress is a much-appreciated phenomenon associated with the progression of neurodegenerative diseases (NDDs) due to imbalances in redox homeostasis. The poor correlations between the in vitro benefits and clinical trials of direct radical scavengers have prompted research into indirect antioxidant enzymes such as Nrf2. Activation of Nrf2 leads to the upregulation of a myriad of cytoprotective and antioxidant enzymes/proteins. Traditionally, early Nrf2-activators were studied as chemoprotective agents. There is a consequential lack of clinical trials testing Nrf2 activation in NDDs. However, there is abundant evidence of their utility in pre-clinical studies. Herein, we review the endogenous Nrf2 regulatory pathway and avenues for targeting this pathway. Furthermore, we provide updated information on preclinical studies for natural and synthetic Nrf2 activators. On the basis of our findings, we posit that successful therapeutics for NDDs rely on the design of potent synthetic Nrf2 activators with a careful combination of other neuroprotective activities.

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Cysteine-based regulation of the CUL3 adaptor protein Keap1

Cited by 137 publications

References 56 publications

12-Lipoxygenase Promotes Obesity-Induced Oxidative Stress in Pancreatic Islets

12-Lipoxygenase Promotes Obesity-Induced Oxidative Stress in Pancreatic Islets

Toll-Like Receptor Signaling Induces Nrf2 Pathway Activation through p62-Triggered Keap1 Degradation

The role of modulation of antioxidant enzyme systems in the treatment of neurodegenerative diseases

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