Cysteine Sulfenylation Directs IRE-1 to Activate the SKN-1/Nrf2 Antioxidant Response

Hourihan, John M.; Mazzeo, Lorenza E Moronetti; Fernández-Cárdenas, Laura Paulette; Blackwell, T. Keith

doi:10.1016/j.molcel.2016.07.019

Cited by 172 publications

(221 citation statements)

References 74 publications

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“…The beneficial effects of low-dose mitochondrial ROS on healthspan and lifespan arise from a hormetic adaptation to mild stress (Hekimi et al, 2011; Shadel, 2014; Ristow and Schmeisser, 2014). Similarly, it was shown recently that ROS production arising from perturbed ER redox homeostasis leads to a protective response that increases lifespan (Hourihan et al, 2016). In each of these examples, mutants that lack the capacity to detoxify ROS (e.g.…”

Section: Discussionmentioning

confidence: 91%

“…RNAi-mediated memo-1 knockdown caused a significant increase in nuclear SKN-1::GFP (Figure 2C and D). Under oxidative stress conditions, SKN-1 phosphorylation/activation is mediated by p38 mitogen-activated protein kinase (MAPK; [Inoue et al, 2005]), which is phosphorylated and activated by SEK-1/MAPKK (Inoue et al, 2005; Hourihan et al, 2016). Importantly, reducing memo-1 function either by RNAi or mutation resulted in higher levels of phospho-p38 MAPK (Figure 2E and F), and loss of sek-1 completely abolished memo-1(-) mediated-longevity (Figure 2G).…”

Section: Resultsmentioning

confidence: 99%

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NADPH oxidase-mediated redox signaling promotes oxidative stress resistance and longevity through memo-1 in C. elegans

Ewald

Hourihan

Bland

et al. 2017

eLife

103

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Transient increases in mitochondrially-derived reactive oxygen species (ROS) activate an adaptive stress response to promote longevity. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases produce ROS locally in response to various stimuli, and thereby regulate many cellular processes, but their role in aging remains unexplored. Here, we identified the C. elegans orthologue of mammalian mediator of ErbB2-driven cell motility, MEMO-1, as a protein that inhibits BLI-3/NADPH oxidase. MEMO-1 is complexed with RHO-1/RhoA/GTPase and loss of memo-1 results in an enhanced interaction of RHO-1 with BLI-3/NADPH oxidase, thereby stimulating ROS production that signal via p38 MAP kinase to the transcription factor SKN-1/NRF1,2,3 to promote stress resistance and longevity. Either loss of memo-1 or increasing BLI-3/NADPH oxidase activity by overexpression is sufficient to increase lifespan. Together, these findings demonstrate that NADPH oxidase-induced redox signaling initiates a transcriptional response that protects the cell and organism, and can promote both stress resistance and longevity.DOI: http://dx.doi.org/10.7554/eLife.19493.001

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Section: Discussionmentioning

confidence: 91%

Section: Resultsmentioning

confidence: 99%

NADPH oxidase-mediated redox signaling promotes oxidative stress resistance and longevity through memo-1 in C. elegans

Ewald

Hourihan

Bland

et al. 2017

eLife

103

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“…However, very high concentrations of metformin (5 m m ) were required to observe significant inhibition of mitochondrion respiratory chain complex 1 activity (He & Wondisford, 2015). Recent studies showed that Nrf2 can be activated by the ER unfolded protein response sensors IRE1α (Hourihan, Moronetti Mazzeo, Fernandez‐Cardenas, & Blackwell, 2016) and PERK (Cullinan et al., 2003). However, in our hands, PERK activation was not detected when HDFs were treated with 100 μ m metformin (Fig.…”

Section: Discussionmentioning

confidence: 99%

Metformin alleviates human cellular aging by upregulating the endoplasmic reticulum glutathione peroxidase 7

et al. 2018

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SummaryMetformin, an FDA‐approved antidiabetic drug, has been shown to elongate lifespan in animal models. Nevertheless, the effects of metformin on human cells remain unclear. Here, we show that low‐dose metformin treatment extends the lifespan of human diploid fibroblasts and mesenchymal stem cells. We report that a low dose of metformin upregulates the endoplasmic reticulum‐localized glutathione peroxidase 7 (GPx7). GP×7 expression levels are decreased in senescent human cells, and GPx7 depletion results in premature cellular senescence. We also indicate that metformin increases the nuclear accumulation of nuclear factor erythroid 2‐related factor 2 (Nrf2), which binds to the antioxidant response elements in the GPX7 gene promoter to induce its expression. Moreover, the metformin‐Nrf2‐GPx7 pathway delays aging in worms. Our study provides mechanistic insights into the beneficial effects of metformin on human cellular aging and highlights the importance of the Nrf2‐GPx7 pathway in pro‐longevity signaling.

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“…Interestingly, in C. elegans and human cells, new evidence suggests that cysteine sulfenylation of IRE1 kinase at its activation loop inhibits IRE1-mediated UPR and initiates a p38 antioxidant response driven by NRF2. The data suggest that IRE1 has an ancient function as a cytoplasmic sentinel that activates p38 and NRF2 [50].…”

Section: Nrf2 Participates In the Unfolded Protein Response (Upr)mentioning

confidence: 89%

Modulation of proteostasis by transcription factor NRF2 and impact in neurodegenerative diseases

2017

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Neurodegenerative diseases are linked to the accumulation of specific protein aggregates, suggesting an intimate connection between injured brain and loss of proteostasis. Proteostasis refers to all the processes by which cells control the abundance and folding of the proteome thanks to a wide network that integrates the regulation of signaling pathways, gene expression and protein degradation systems. This review attempts to summarize the most relevant findings about the transcriptional modulation of proteostasis exerted by the transcription factor NRF2 (nuclear factor (erythroid-derived 2)-like 2). NRF2 has been classically considered as the master regulator of the antioxidant cell response, although it is currently emerging as a key component of the transduction machinery to maintain proteostasis. As we will discuss, NRF2 could be envisioned as a hub that compiles emergency signals derived from misfolded protein accumulation in order to build a coordinated and perdurable transcriptional response. This is achieved by functions of NRF2 related to the control of genes involved in the maintenance of the endoplasmic reticulum physiology, the proteasome and autophagy.

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Cysteine Sulfenylation Directs IRE-1 to Activate the SKN-1/Nrf2 Antioxidant Response

Cited by 172 publications

References 74 publications

NADPH oxidase-mediated redox signaling promotes oxidative stress resistance and longevity through memo-1 in C. elegans

NADPH oxidase-mediated redox signaling promotes oxidative stress resistance and longevity through memo-1 in C. elegans

Metformin alleviates human cellular aging by upregulating the endoplasmic reticulum glutathione peroxidase 7

Modulation of proteostasis by transcription factor NRF2 and impact in neurodegenerative diseases

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