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

Steinbaugh MJ, Narasimhan SD, Robida-Stubbs S, Moronetti Mazzeo LE, Dreyfuss JM, Hourihan JM, Raghavan P, Operaña TN, Esmaillie R, Blackwell TK - Elife (2015)

Bottom Line: Surprisingly, SKN-1 is activated by signals from this fat, which appears to derive from unconsumed yolk that was produced for reproduction.We conclude that SKN-1 plays a direct role in maintaining lipid homeostasis in which it is activated by lipids.This SKN-1 function may explain the importance of mammalian Nrf proteins in fatty liver disease and suggest that particular endogenous or dietary lipids might promote health through SKN-1/Nrf.

View Article: PubMed Central - PubMed

Affiliation: Research Division, Joslin Diabetes Center, Boston, United States.

ABSTRACT
In Caenorhabditis elegans, ablation of germline stem cells (GSCs) extends lifespan, but also increases fat accumulation and alters lipid metabolism, raising the intriguing question of how these effects might be related. Here, we show that a lack of GSCs results in a broad transcriptional reprogramming in which the conserved detoxification regulator SKN-1/Nrf increases stress resistance, proteasome activity, and longevity. SKN-1 also activates diverse lipid metabolism genes and reduces fat storage, thereby alleviating the increased fat accumulation caused by GSC absence. Surprisingly, SKN-1 is activated by signals from this fat, which appears to derive from unconsumed yolk that was produced for reproduction. We conclude that SKN-1 plays a direct role in maintaining lipid homeostasis in which it is activated by lipids. This SKN-1 function may explain the importance of mammalian Nrf proteins in fatty liver disease and suggest that particular endogenous or dietary lipids might promote health through SKN-1/Nrf.

No MeSH data available.


Related in: MedlinePlus

SKN-1-dependence of the increased proteasome activity in GSC(−) animals.(A) GSC absence reduces relative proteasome subunit gene mRNA abundance, detected by RNA-seq. (B, C) The skn-1(zu135) mutation suppresses the increase in 26S proteasome activity seen in day-1 adult glp-1(ts) animals. (D, E) skn-1 RNAi administered from the egg stage suppresses proteasome activity in day-1 adult glp-1(ts) animals. (F, G) skn-1 RNAi administered post-developmentally, starting at day-1 adulthood, significantly reduces proteasome activity in day-5 adult glp-1(ts) animals. (B, D, F) Kinetic curves of chymotrypsin-like proteasome activity. (C, E, G) Graphs of proteasome activity slopes. Data are represented as mean ± SEM. n = 3; p < 0.001***.DOI:http://dx.doi.org/10.7554/eLife.07836.010
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fig4s1: SKN-1-dependence of the increased proteasome activity in GSC(−) animals.(A) GSC absence reduces relative proteasome subunit gene mRNA abundance, detected by RNA-seq. (B, C) The skn-1(zu135) mutation suppresses the increase in 26S proteasome activity seen in day-1 adult glp-1(ts) animals. (D, E) skn-1 RNAi administered from the egg stage suppresses proteasome activity in day-1 adult glp-1(ts) animals. (F, G) skn-1 RNAi administered post-developmentally, starting at day-1 adulthood, significantly reduces proteasome activity in day-5 adult glp-1(ts) animals. (B, D, F) Kinetic curves of chymotrypsin-like proteasome activity. (C, E, G) Graphs of proteasome activity slopes. Data are represented as mean ± SEM. n = 3; p < 0.001***.DOI:http://dx.doi.org/10.7554/eLife.07836.010

Mentions: A previous RNAi experiment suggested that SKN-1 is dispensable for the elevated proteasome activity seen in GSC(−) animals (Vilchez et al., 2012). We re-examined this question because SKN-1 maintains proteasome gene expression and intestinal proteasome activity in WT C. elegans (Li et al., 2011), and because proteasome genes were prominent in the SKN-1-upregulated GSC(−) gene set (Supplementary file 1c). The proteasome holocomplex consists of a 20S barrel-like structure in which proteins are degraded, and a 19S regulatory cap that directs ubiquitylated proteins into this structure (Glickman and Ciechanover, 2002; Goldberg, 2003). In general, and consistent with previous findings (Vilchez et al., 2012), the relative levels of proteasome subunit mRNAs were lower in GSC(−) animals (Figure 4—figure supplement 1A), possibly because of the lack of germ cells. In both WT and GSC(−) animals, skn-1 knockdown comparably decreased expression of 19S and 20S proteasome subunit genes (Figure 4A and Figure 4—figure supplement 1A), the majority of which appear to be direct transcriptional targets of SKN-1 (Figure 4B). As these findings would predict, in GSC(−) animals, the lack of skn-1 dramatically reduced proteasome activity at days 1 and 5 of adulthood (Figure 4C,D, and Figure 4—figure supplement 1B–G). It is possible that in the earlier analysis (Vilchez et al., 2012), RNAi might not have inhibited skn-1 expression sufficiently to detect its importance for proteasome activity in GSC(−) animals.10.7554/eLife.07836.009Figure 4.SKN-1 increases proteasome activity in response to GSC absence.


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

Steinbaugh MJ, Narasimhan SD, Robida-Stubbs S, Moronetti Mazzeo LE, Dreyfuss JM, Hourihan JM, Raghavan P, Operaña TN, Esmaillie R, Blackwell TK - Elife (2015)

SKN-1-dependence of the increased proteasome activity in GSC(−) animals.(A) GSC absence reduces relative proteasome subunit gene mRNA abundance, detected by RNA-seq. (B, C) The skn-1(zu135) mutation suppresses the increase in 26S proteasome activity seen in day-1 adult glp-1(ts) animals. (D, E) skn-1 RNAi administered from the egg stage suppresses proteasome activity in day-1 adult glp-1(ts) animals. (F, G) skn-1 RNAi administered post-developmentally, starting at day-1 adulthood, significantly reduces proteasome activity in day-5 adult glp-1(ts) animals. (B, D, F) Kinetic curves of chymotrypsin-like proteasome activity. (C, E, G) Graphs of proteasome activity slopes. Data are represented as mean ± SEM. n = 3; p < 0.001***.DOI:http://dx.doi.org/10.7554/eLife.07836.010
© Copyright Policy
Related In: Results  -  Collection

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fig4s1: SKN-1-dependence of the increased proteasome activity in GSC(−) animals.(A) GSC absence reduces relative proteasome subunit gene mRNA abundance, detected by RNA-seq. (B, C) The skn-1(zu135) mutation suppresses the increase in 26S proteasome activity seen in day-1 adult glp-1(ts) animals. (D, E) skn-1 RNAi administered from the egg stage suppresses proteasome activity in day-1 adult glp-1(ts) animals. (F, G) skn-1 RNAi administered post-developmentally, starting at day-1 adulthood, significantly reduces proteasome activity in day-5 adult glp-1(ts) animals. (B, D, F) Kinetic curves of chymotrypsin-like proteasome activity. (C, E, G) Graphs of proteasome activity slopes. Data are represented as mean ± SEM. n = 3; p < 0.001***.DOI:http://dx.doi.org/10.7554/eLife.07836.010
Mentions: A previous RNAi experiment suggested that SKN-1 is dispensable for the elevated proteasome activity seen in GSC(−) animals (Vilchez et al., 2012). We re-examined this question because SKN-1 maintains proteasome gene expression and intestinal proteasome activity in WT C. elegans (Li et al., 2011), and because proteasome genes were prominent in the SKN-1-upregulated GSC(−) gene set (Supplementary file 1c). The proteasome holocomplex consists of a 20S barrel-like structure in which proteins are degraded, and a 19S regulatory cap that directs ubiquitylated proteins into this structure (Glickman and Ciechanover, 2002; Goldberg, 2003). In general, and consistent with previous findings (Vilchez et al., 2012), the relative levels of proteasome subunit mRNAs were lower in GSC(−) animals (Figure 4—figure supplement 1A), possibly because of the lack of germ cells. In both WT and GSC(−) animals, skn-1 knockdown comparably decreased expression of 19S and 20S proteasome subunit genes (Figure 4A and Figure 4—figure supplement 1A), the majority of which appear to be direct transcriptional targets of SKN-1 (Figure 4B). As these findings would predict, in GSC(−) animals, the lack of skn-1 dramatically reduced proteasome activity at days 1 and 5 of adulthood (Figure 4C,D, and Figure 4—figure supplement 1B–G). It is possible that in the earlier analysis (Vilchez et al., 2012), RNAi might not have inhibited skn-1 expression sufficiently to detect its importance for proteasome activity in GSC(−) animals.10.7554/eLife.07836.009Figure 4.SKN-1 increases proteasome activity in response to GSC absence.

Bottom Line: Surprisingly, SKN-1 is activated by signals from this fat, which appears to derive from unconsumed yolk that was produced for reproduction.We conclude that SKN-1 plays a direct role in maintaining lipid homeostasis in which it is activated by lipids.This SKN-1 function may explain the importance of mammalian Nrf proteins in fatty liver disease and suggest that particular endogenous or dietary lipids might promote health through SKN-1/Nrf.

View Article: PubMed Central - PubMed

Affiliation: Research Division, Joslin Diabetes Center, Boston, United States.

ABSTRACT
In Caenorhabditis elegans, ablation of germline stem cells (GSCs) extends lifespan, but also increases fat accumulation and alters lipid metabolism, raising the intriguing question of how these effects might be related. Here, we show that a lack of GSCs results in a broad transcriptional reprogramming in which the conserved detoxification regulator SKN-1/Nrf increases stress resistance, proteasome activity, and longevity. SKN-1 also activates diverse lipid metabolism genes and reduces fat storage, thereby alleviating the increased fat accumulation caused by GSC absence. Surprisingly, SKN-1 is activated by signals from this fat, which appears to derive from unconsumed yolk that was produced for reproduction. We conclude that SKN-1 plays a direct role in maintaining lipid homeostasis in which it is activated by lipids. This SKN-1 function may explain the importance of mammalian Nrf proteins in fatty liver disease and suggest that particular endogenous or dietary lipids might promote health through SKN-1/Nrf.

No MeSH data available.


Related in: MedlinePlus