Depletion of a nucleolar protein activates xenobiotic detoxification genes in Caenorhabditis elegans via Nrf /SKN-1 and p53/CEP-1

Leung, Chi-Wai; Empinado, Hyacinth; Choe, Keith P.

doi:10.1016/j.freeradbiomed.2011.12.009

Cited by 16 publications

(18 citation statements)

References 63 publications

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“…Xenobiotic response mutations cause SKN-1 to translocate into the nucleus. Previous studies with transgenic SKN-1::GFP fusion proteins expressed from multicopy arrays suggest that SKN-1 is regulated in part by nuclear translocation (7,8,29,39). We previously demonstrated that the loss of wdr-23 increases the nuclear abundance of SKN-1::GFP (8).…”

Section: Wdr-23 May Preferentially Regulate Skn-1cmentioning

confidence: 95%

Direct Interaction between the WD40 Repeat Protein WDR-23 and SKN-1/Nrf Inhibits Binding to Target DNA

Leung

Hasegawa

Wang

et al. 2014

Molecular and Cellular Biology

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c SKN-1/Nrf transcription factors activate cytoprotective genes in response to reactive small molecules and strongly influence stress resistance, longevity, and development. The molecular mechanisms of SKN-1/Nrf regulation are poorly defined. We previously identified the WD40 repeat protein WDR-23 as a repressor of Caenorhabditis elegans SKN-1 that functions with a ubiquitin ligase to presumably target the factor for degradation. However, SKN-1 activity and nuclear accumulation are not always correlated, suggesting that there could be additional regulatory mechanisms. Here, we integrate forward genetics and biochemistry to gain insights into how WDR-23 interacts with and regulates SKN-1. We provide evidence that WDR-23 preferentially regulates one of three SKN-1 variants through a direct interaction that is required for normal stress resistance and development. Homology modeling predicts that WDR-23 folds into a ␤-propeller, and we identify the top of this structure and four motifs at the termini of SKN-1c as essential for the interaction. Two of these SKN-1 motifs are highly conserved in human Nrf1 and Nrf2 and two directly interact with target DNA. Lastly, we demonstrate that WDR-23 can block the ability of SKN-1c to interact with DNA sequences of target promoters identifying a new mechanism of regulation that is independent of the ubiquitin proteasome system, which can become occupied with damaged proteins during stress.

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Section: Wdr-23 May Preferentially Regulate Skn-1cmentioning

confidence: 95%

Direct Interaction between the WD40 Repeat Protein WDR-23 and SKN-1/Nrf Inhibits Binding to Target DNA

Leung

Hasegawa

Wang

et al. 2014

Molecular and Cellular Biology

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“…To confirm that the single-copy insertions were functional and to monitor SKN-1 activity in vivo, both single-copy wdr-23 insertions and wdr-23(tm1817) were crossed with a widely used GFP transcriptional reporter for the SKN-1 target gene, gst-4 (21,28,53). Pgst-4::GFP fluorescence is extremely bright in wdr-23(tm1817) worms due to nearly complete derepression of SKN-1 (21).…”

Section: R E T R a C T E Dmentioning

confidence: 99%

“…Previous studies demonstrated that SKN-1 promotes stress resistance and longevity in wild-type C. elegans and in mutants with reduced insulin signaling or protein translation (9)(10)(11)28). Nrf2 in mammals also promotes stress resistance and is associated with some strains of long-lived mice (12).…”

Section: R E T R a C T E Dmentioning

confidence: 99%

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A Negative-Feedback Loop between the Detoxification/Antioxidant Response Factor SKN-1 and Its Repressor WDR-23 Matches Organism Needs with Environmental Conditions

Leung

Wang

Deonarine

et al. 2013

Molecular and Cellular Biology

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Negative-feedback loops between transcription factors and repressors in responses to xenobiotics, oxidants, heat, hypoxia, DNA damage, and infection have been described. Although common, the function of feedback is largely unstudied. Here, we define a negative-feedback loop between the Caenorhabditis elegans detoxification/antioxidant response factor SKN-1/Nrf and its repressor wdr-23 and investigate its function in vivo. Although SKN-1 promotes stress resistance and longevity, we find that tight regulation by WDR-23 is essential for growth and reproduction. By disabling SKN-1 transactivation of wdr-23, we reveal that feedback is required to set the balance between growth/reproduction and stress resistance/longevity. We also find that feedback is required to set the sensitivity of a core SKN-1 target gene to an electrophile. Interestingly, the effect of feedback on target gene induction is greatly reduced when the stress response is strongly activated, presumably to ensure maximum activation of cytoprotective genes during potentially fatal conditions. Our work provides a framework for understanding the function of negative feedback in inducible stress responses and demonstrates that manipulation of feedback alone can shift the balance of competing animal processes toward cell protection, health, and longevity. P rotective responses to cellular stress are coordinated by inducible transcription factors. Tight regulation of stress responses is essential, because they may have consequences for important processes such as growth, development, and reproduction. Negative feedback is a fundamental strategy for regulation of homeostatic processes at all levels of physiology. Simple two-component negative-feedback loops in which a transcription factor induces the expression of an interacting protein that represses the transcription factor are found within responses to diverse stressors, including DNA damage (1), oxidants (2), hypoxia (3), heat shock (4), and infection (5). Although the general importance of repression is recognized, the regulatory and physiological importance of feedback is unexplored.The Cap 'n' Collar (CNC) family of transcription factors orchestrates inducible antioxidant and detoxification responses in animal cells (6). CNC factors activate the expression of genes encoding enzymes that scavenge free radicals, synthesize glutathione, detoxify and export xenobiotics, and repair damage to proteins (6, 7). CNCs promote longevity in invertebrate models (8-11), and increased CNC activity is associated with long-lived and stress-resistant strains of mice (12). The main inducible CNC in humans is Nrf2, which is a popular chemopreventative target for diverse pathologies, including cancer, neurodegeneration, inflammation, asthma, and aging (13-16).Nrf2 is an unstable protein that is targeted for degradation by KEAP1, a Kelch repeat protein that functions as an adaptor for the CUL3 ubiquitin ligase. Oxidative modification of KEAP1 releases Nrf2 and allows it to accumulate and activate a cytoprotective gene expre...

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“…It may also ensure that redox homeostasis in the cytosol is compatible with redox-dependent protein processing in the ER. The activity of SKN-1 also responds to changes in the nucleolus [17], the proteasomes [18], nutrient signaling [5]–[6], and protein translation [19]. Therefore, an extremely complex network of signals likely converges on SKN-1 to ensure that redox status and detoxification activity are compatible with a number of cellular processes.…”

mentioning

confidence: 99%

SKN-1/Nrf, A New Unfolded Protein Response Factor?

Choe

Leung

2013

PLoS Genet

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Depletion of a nucleolar protein activates xenobiotic detoxification genes in Caenorhabditis elegans via Nrf /SKN-1 and p53/CEP-1

Cited by 16 publications

References 63 publications

Direct Interaction between the WD40 Repeat Protein WDR-23 and SKN-1/Nrf Inhibits Binding to Target DNA

Direct Interaction between the WD40 Repeat Protein WDR-23 and SKN-1/Nrf Inhibits Binding to Target DNA

A Negative-Feedback Loop between the Detoxification/Antioxidant Response Factor SKN-1 and Its Repressor WDR-23 Matches Organism Needs with Environmental Conditions

SKN-1/Nrf, A New Unfolded Protein Response Factor?

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