Lipid-mediated regulation of SKN-1/Nrf in response to germ cell absence

Steinbaugh, Michael J.; Narasimhan, Sri Devi; Robida-Stubbs, Stacey; Mazzeo, Lorenza E Moronetti; Dreyfuss, Jonathan M.; Hourihan, John M.; Raghavan, Prashant; Operaña, Theresa N.; Esmaillie, Reza; Blackwell, T. Keith

doi:10.7554/elife.07836

Cited by 187 publications

(313 citation statements)

References 109 publications

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“…Both ROS and H 2 S are known to activate Nrf2 (36); in particular, H 2 S has been shown to extend worm lifespan via increased SKN-1/Nrf2 activity (37). We tested skn-1 and found, as have others recently (38), that expression of the glutathione-Stransferase reporter Pgst-4::GFP, a direct target of SKN-1, was induced upon loss of germ cells in C. elegans in a skn-1-dependent fashion ( Fig. 3 A and B and SI Appendix, Fig.…”

Section: Resultsmentioning

confidence: 99%

Roles for ROS and hydrogen sulfide in the longevity response to germline loss in Caenorhabditis elegans

Wei

Kenyon

2016

Proc. Natl. Acad. Sci. U.S.A.

110

125

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In Caenorhabditis elegans, removing germ cells slows aging and extends life. Here we show that transcription factors that extend life and confer protection to age-related protein-aggregation toxicity are activated early in adulthood in response to a burst of reactive oxygen species (ROS) and a shift in sulfur metabolism. Germline loss triggers H 2 S production, mitochondrial biogenesis, and a dynamic pattern of ROS in specific somatic tissues. A cytoskeletal protein, KRI-1, plays a key role in the generation of H 2 S and ROS. These kri-1-dependent redox species, in turn, promote life extension by activating SKN-1/Nrf2 and the mitochondrial unfolded-protein response, respectively. Both H 2 S and, remarkably, kri-1-dependent ROS are required for the life extension produced by low levels of the superoxide-generator paraquat and by a mutation that inhibits respiration. Together our findings link reproductive signaling to mitochondria and define an inducible, kri-1-dependent redox-signaling module that can be invoked in different contexts to extend life and counteract proteotoxicity.

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Section: Resultsmentioning

confidence: 99%

Roles for ROS and hydrogen sulfide in the longevity response to germline loss in Caenorhabditis elegans

Wei

Kenyon

2016

Proc. Natl. Acad. Sci. U.S.A.

110

125

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“…The SKN-1-controlled acute transcriptional response to oxidative stress and reactive electrophilic compounds is wellconserved between species and has been extensively documented before. [1][2][3][4][5] More recently, SKN-1 has been implicated in much broader homeostatic functions, 2 such as coordinating a distinct response to alleviate ER stress, 6 counteracting excessive lipid accumulation 7 and controlling mitochondrial biogenesis and mitophagy. 8 Regulatory integration through SKN-1 is now believed to continuously coordinate ER, mitochondrial and cytoplasmic homeostasis.…”

Section: Introductionmentioning

confidence: 99%

SKN-1-independent transcriptional activation of glutathione S-transferase 4 (GST-4) by EGF signaling

Detienne

Walle

Haes

et al. 2016

Worm

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In C. elegans research, transcriptional activation of glutathione S-transferase 4 (gst-4) is often used as a read-out for SKN-1 activity. While many heed an assumed non-exclusivity of the GFP reporter signal driven by the gst-4 promoter to SKN-1, this is also often ignored. We here show that gst-4 can also be transcriptionally activated by EOR-1, a transcription factor mediating effects of the epidermal growth factor (EGF) pathway. Along with enhancing exogenous oxidative stress tolerance, EOR-1 independently of SKN-1 increases gst-4 transcription in response to augmented EGF signaling.Our findings caution researchers within the C. elegans community to always rely on sufficient experimental controls when assaying SKN-1 transcriptional activity with a gst-4 p ::gfp reporter, such as SKN-1 loss-of-function mutants and/or additional target genes next to gst-4.

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“…4) may result from excess, unutilized yolk production. To test this hypothesis, we asked whether worms with mutations in the transcription factor skn-1, recently reported to be important for the digestion of yolk fat in the adult worm (Steinbaugh et al 2015), had any effect on Avid rates. The results show that loss of skn-1 activity, with the accompanying loss of yolk digestion, leads to a dramatic increase in Avid rates (Fig.…”

Section: Resultsmentioning

confidence: 99%

Age-associated vulval integrity is an important marker of nematode healthspan

Leiser

Jafari

Primitivo

et al. 2016

AGE

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Improving healthspan, defined as the period where organisms live without frailty and/or disease, is a major goal of biomedical research. While healthspan measures in people are relatively easy to identify, developing robust markers of healthspan in model organisms has proven challenging. Studies using the nematode Caenorhabditis elegans have provided vital information on the basic mechanisms of aging; however, worm health is difficult to define, and the impact of interventions that increase lifespan on worm healthspan has been controversial. Here, we describe a marker of population healthspan in C. elegans that we term age-associated vulval integrity defects, or Avid, frequently described elsewhere as rupture or exploding. We connect the presence of this phenotype with temperature, reproduction, diet, and longevity. Our results show that Avid occurs in post-reproductive worms under common laboratory conditions at a frequency that correlates negatively with temperature; Avid is rare in worms kept at 25°C and more frequent in worms kept at 15°C. We describe the kinetics of Avid, link the phenotype to oocyte production, and describe how Avid involves the ejection of worm proteins and/or internal organ(s) from the vulva. Finally, we find that Avid is preventable by removing worms from food, suggesting that Avid results from the intake, digestion, and/or absorption of food. Our results show that Avid is a significant cause of death in worm populations maintained under laboratory conditions and that its prevention often correlates with worm longevity. We propose that Avid is a powerful marker of worm healthspan whose underlying molecular mechanisms may be conserved.

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Lipid-mediated regulation of SKN-1/Nrf in response to germ cell absence

Cited by 187 publications

References 109 publications

Roles for ROS and hydrogen sulfide in the longevity response to germline loss in Caenorhabditis elegans

Roles for ROS and hydrogen sulfide in the longevity response to germline loss in Caenorhabditis elegans

SKN-1-independent transcriptional activation of glutathione S-transferase 4 (GST-4) by EGF signaling

Age-associated vulval integrity is an important marker of nematode healthspan

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