SKN-1 regulates stress resistance downstream of amino catabolism pathways

Frankino, Phillip A.; Siddiqi, Talha F.; Bolas, Theodore; Bar‐Ziv, Raz; Gildea, Holly K.; Zhang, Hanlin; Higuchi‐Sanabria, Ryo; Dillin, Andrew

doi:10.1016/j.isci.2022.104571

Cited by 9 publications

(6 citation statements)

References 51 publications

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“…Perturbation of amino acid catabolic pathways, such as proline catabolism, leads to a buildup of toxic catabolites, triggering SKN-1-related transcription through ROS accumulation ( Pang et al, 2014 ; Yen et al, 2020 ). Similar SKN-1 transcriptional responses have been reported with perturbations of tryptophan, threonine, and most recently, histidine catabolism ( Frankino et al, 2022 ). In a study by Frankino et al (2022), knockdown of the conserved amidohydrolase T12A2.1/ amdh-1 results in the accumulation of the catabolite 4-imidazolone-5-propanoate, serving as a mediator for the activation of a specific subset of SKN-1-regulated genes.…”

Section: Modulators Of Skn-1 Activitysupporting

confidence: 79%

Disrupting the SKN-1 homeostat: mechanistic insights and phenotypic outcomes

Turner,

Ramos,

Curran

2024

Front. Aging

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The mechanisms that govern maintenance of cellular homeostasis are crucial to the lifespan and healthspan of all living systems. As an organism ages, there is a gradual decline in cellular homeostasis that leads to senescence and death. As an organism lives into advanced age, the cells within will attempt to abate age-related decline by enhancing the activity of cellular stress pathways. The regulation of cellular stress responses by transcription factors SKN-1/Nrf2 is a well characterized pathway in which cellular stress, particularly xenobiotic stress, is abated by SKN-1/Nrf2-mediated transcriptional activation of the Phase II detoxification pathway. However, SKN-1/Nrf2 also regulates a multitude of other processes including development, pathogenic stress responses, proteostasis, and lipid metabolism. While this process is typically tightly regulated, constitutive activation of SKN-1/Nrf2 is detrimental to organismal health, this raises interesting questions surrounding the tradeoff between SKN-1/Nrf2 cryoprotection and cellular health and the ability of cells to deactivate stress response pathways post stress. Recent work has determined that transcriptional programs of SKN-1 can be redirected or suppressed to abate negative health outcomes of constitutive activation. Here we will detail the mechanisms by which SKN-1 is controlled, which are important for our understanding of SKN-1/Nrf2 cytoprotection across the lifespan.

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Section: Modulators Of Skn-1 Activitysupporting

confidence: 79%

Disrupting the SKN-1 homeostat: mechanistic insights and phenotypic outcomes

Turner,

Ramos,

Curran

2024

Front. Aging

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“…Increasing evidence support the implication of SKN‐1/Nrf in metabolic surveillance, including responses to excessive metabolites, disease proteins, aging stress, and xenobiotic insults, despite being originally discovered as an antioxidant transcription factor (Blackwell et al., 2015 ; Dodson et al., 2019 ; Frankino et al., 2022 ; Peters et al., 2021 ). In this study, a large number of AbaPep#07‐regulated genes are the reported targets or contain predicted binding sites of SKN‐1/Nrf, including many of the differentially expressed genes in immune defense (26 out of 85) and lipid metabolism (13 out of 26) as well as the majority of the 40 regulated genes in the three phases of metabolic detoxification (Figure 5 , Figure 6 , and Table S7 ).…”

Section: Discussionmentioning

confidence: 99%

Abalone peptide increases stress resilience and cost‐free longevity via SKN‐1‐governed transcriptional metabolic reprogramming in C. elegans

Wang,

Huang

et al. 2023

Aging Cell

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A major goal of healthy aging is to prevent declining resilience and increasing frailty, which are associated with many chronic diseases and deterioration of stress response. Here, we propose a loss‐or‐gain survival model, represented by the ratio of cumulative stress span to life span, to quantify stress resilience at organismal level. As a proof of concept, this is demonstrated by reduced survival resilience in Caenorhabditis elegans exposed to exogenous oxidative stress induced by paraquat or with endogenous proteotoxic stress caused by polyglutamine or amyloid‐β aggregation. Based on this, we reveal that a hidden peptide (“cryptide”)—AbaPep#07 (SETYELRK)—derived from abalone hemocyanin not only enhances survival resilience against paraquat‐induced oxidative stress but also rescues proteotoxicity‐mediated behavioral deficits in C. elegans, indicating its capacity against stress and neurodegeneration. Interestingly, AbaPep#07 is also found to increase cost‐free longevity and age‐related physical fitness in nematodes. We then demonstrate that AbaPep#07 can promote nuclear localization of SKN‐1/Nrf, but not DAF‐16/FOXO, transcription factor. In contrast to its effects in wild‐type nematodes, AbaPep#07 cannot increase oxidative stress survival and physical motility in loss‐of‐function skn‐1 mutant, suggesting an SKN‐1/Nrf‐dependent fashion of these effects. Further investigation reveals that AbaPep#07 can induce transcriptional activation of immune defense, lipid metabolism, and metabolic detoxification pathways, including many SKN‐1/Nrf target genes. Together, our findings demonstrate that AbaPep#07 is able to boost stress resilience and reduce behavioral frailty via SKN‐1/Nrf‐governed transcriptional reprogramming, and provide an insight into the health‐promoting potential of antioxidant cryptides as geroprotectors in aging and associated conditions.

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“…2014 ; Hou et al . 2014 ; Frankino et al . 2022 ), as well as mdt-15 knockdowns activating hsp-4 expression ( Hou et al .…”

Section: Discussionmentioning

confidence: 99%

A transcriptional cofactor regulatory network for the C. elegans intestine

Horowitz

Nanda

Walhout

2023

G3: Genes, Genomes, Genetics

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Chromatin modifiers and transcriptional cofactors (collectively referred to as CFs) work with DNA-binding transcription factors (TFs) to regulate gene expression. In multicellular eukaryotes, distinct tissues each execute their own gene expression program for accurate differentiation and subsequent functionality. While the function of TFs in differential gene expression has been studied in detail in many systems, the contribution of CFs has remained less explored. Here, we uncovered the contributions of CFs to gene regulation in the Caenorhabditis elegans intestine. We first annotated 366 CFs encoded by the C. elegans genome and assembled a library of 335 RNAi clones. Using this library, we analyzed the effects of individually depleting these CFs on the expression of 19 fluorescent transcriptional reporters in the intestine and identified 216 regulatory interactions. We found that different CFs regulate different promoters, and that both essential and intestinally expressed CFs have the greatest effects on promoter activity. We did not find all members of CF complexes acting on the same set of reporters but instead found diversity in the promoter targets of each complex component. Finally, we found that previously identified activation mechanisms for the acdh-1 promoter use different CFs and TFs. Overall, we demonstrate that CFs function specifically rather than ubiquitously at intestinal promoters and provide an RNAi resource for reverse genetic screens.

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SKN-1 regulates stress resistance downstream of amino catabolism pathways

Cited by 9 publications

References 51 publications

Disrupting the SKN-1 homeostat: mechanistic insights and phenotypic outcomes

Disrupting the SKN-1 homeostat: mechanistic insights and phenotypic outcomes

Abalone peptide increases stress resilience and cost‐free longevity via SKN‐1‐governed transcriptional metabolic reprogramming in C. elegans

A transcriptional cofactor regulatory network for the C. elegans intestine

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