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Specific SKN-1/Nrf stress responses to perturbations in translation elongation and proteasome activity.

Li X, Matilainen O, Jin C, Glover-Cutter KM, Holmberg CI, Blackwell TK - PLoS Genet. (2011)

Bottom Line: In contrast, when translation elongation is impaired, SKN-1 does not upregulate proteasome genes, and UPS activity is then reduced.SKN-1 therefore has a critical tissue-specific function in increasing proteasome gene expression and UPS activity under normal conditions, as well as when the UPS system is stressed, but mounts distinct responses when protein synthesis is perturbed.The data suggest that SKN-1 may increase longevity, not only through its well-documented role in boosting stress resistance, but also through contributing to protein homeostasis.

View Article: PubMed Central - PubMed

Affiliation: Joslin Diabetes Center, Harvard Stem Cell Institute, Harvard Medical School, Boston, Massachusetts, United States of America.

ABSTRACT
SKN-1, the Caenorhabditis elegans Nrf1/2/3 ortholog, promotes both oxidative stress resistance and longevity. SKN-1 responds to oxidative stress by upregulating genes that detoxify and defend against free radicals and other reactive molecules, a SKN-1/Nrf function that is both well-known and conserved. Here we show that SKN-1 has a broader and more complex role in maintaining cellular stress defenses. SKN-1 sustains expression and activity of the ubiquitin-proteasome system (UPS) and coordinates specific protective responses to perturbations in protein synthesis or degradation through the UPS. If translation initiation or elongation is impaired, SKN-1 upregulates overlapping sets of cytoprotective genes and increases stress resistance. When proteasome gene expression and activity are blocked, SKN-1 activates multiple classes of proteasome subunit genes in a compensatory response. SKN-1 thereby maintains UPS activity in the intestine in vivo under normal conditions and promotes survival when the proteasome is inhibited. In contrast, when translation elongation is impaired, SKN-1 does not upregulate proteasome genes, and UPS activity is then reduced. This indicates that UPS activity depends upon presence of an intact translation elongation apparatus; and it supports a model, suggested by genetic and biochemical studies in yeast, that protein synthesis and degradation may be coupled processes. SKN-1 therefore has a critical tissue-specific function in increasing proteasome gene expression and UPS activity under normal conditions, as well as when the UPS system is stressed, but mounts distinct responses when protein synthesis is perturbed. The specificity of these SKN-1-mediated stress responses, along with the apparent coordination between UPS and translation elongation activity, may promote protein homeostasis under stress or disease conditions. The data suggest that SKN-1 may increase longevity, not only through its well-documented role in boosting stress resistance, but also through contributing to protein homeostasis.

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TEF inhibition does not globally induce stress responses.In (A–C), Relative levels of the indicated endogenous mRNAs were assayed by qRT-PCR after RNAi against the indicated TEF, or CHX treatment. N = not significant. In (A), all other P<0.025; in (B), all other P<0.05; in (C), all other P<0.02.
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pgen-1002119-g002: TEF inhibition does not globally induce stress responses.In (A–C), Relative levels of the indicated endogenous mRNAs were assayed by qRT-PCR after RNAi against the indicated TEF, or CHX treatment. N = not significant. In (A), all other P<0.025; in (B), all other P<0.05; in (C), all other P<0.02.

Mentions: It is an important question whether the SKN-1-mediated response to reduced translation elongation might derive simply from a non-specific activation of multiple stress defenses. To test this idea, we investigated how other stress responses involved in protein homeostasis are influenced by TEF RNAi. An accumulation of misfolded proteins in the endoplasmic reticulum (ER) or mitochondria triggers the ER unfolded protein response (UPRer), or mitochondrial UPR (UPRmt), respectively. To investigate whether the UPRer or UPRmt is activated in response to inhibition of TEFs, we examined transcriptional levels of hsp-4, an indicator of the UPRer [31], along with the UPRmt indicators hsp-6 and hsp-60 [32]. In general, TEF RNAi did not robustly increase the levels of hsp-4, hsp-6, or hsp-60 mRNAs (Figure 2A and 2B). Heat shock proteins (HSPs) act as chaperones that cope with misfolded cytoplasmic proteins during multiple stresses. As an indicator of effects on this network, we assayed for induction of genes representing four major classes of heat shock proteins: small HSPs (hsp-16.2), DnaJ/HSP40s (dnj-19, dnj-12), Hsc/HSP70s (hsp-70), and HSP90s (T05E11.3, daf-21) [33]. These HSP genes were also not upregulated in response to inhibition of most TEFs (Figure 2C, Figure S3A and S3B). Taken together, the data indicate that RNAi against TEFs does not broadly activate stress responses involved in proteostasis.


Specific SKN-1/Nrf stress responses to perturbations in translation elongation and proteasome activity.

Li X, Matilainen O, Jin C, Glover-Cutter KM, Holmberg CI, Blackwell TK - PLoS Genet. (2011)

TEF inhibition does not globally induce stress responses.In (A–C), Relative levels of the indicated endogenous mRNAs were assayed by qRT-PCR after RNAi against the indicated TEF, or CHX treatment. N = not significant. In (A), all other P<0.025; in (B), all other P<0.05; in (C), all other P<0.02.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3111486&req=5

pgen-1002119-g002: TEF inhibition does not globally induce stress responses.In (A–C), Relative levels of the indicated endogenous mRNAs were assayed by qRT-PCR after RNAi against the indicated TEF, or CHX treatment. N = not significant. In (A), all other P<0.025; in (B), all other P<0.05; in (C), all other P<0.02.
Mentions: It is an important question whether the SKN-1-mediated response to reduced translation elongation might derive simply from a non-specific activation of multiple stress defenses. To test this idea, we investigated how other stress responses involved in protein homeostasis are influenced by TEF RNAi. An accumulation of misfolded proteins in the endoplasmic reticulum (ER) or mitochondria triggers the ER unfolded protein response (UPRer), or mitochondrial UPR (UPRmt), respectively. To investigate whether the UPRer or UPRmt is activated in response to inhibition of TEFs, we examined transcriptional levels of hsp-4, an indicator of the UPRer [31], along with the UPRmt indicators hsp-6 and hsp-60 [32]. In general, TEF RNAi did not robustly increase the levels of hsp-4, hsp-6, or hsp-60 mRNAs (Figure 2A and 2B). Heat shock proteins (HSPs) act as chaperones that cope with misfolded cytoplasmic proteins during multiple stresses. As an indicator of effects on this network, we assayed for induction of genes representing four major classes of heat shock proteins: small HSPs (hsp-16.2), DnaJ/HSP40s (dnj-19, dnj-12), Hsc/HSP70s (hsp-70), and HSP90s (T05E11.3, daf-21) [33]. These HSP genes were also not upregulated in response to inhibition of most TEFs (Figure 2C, Figure S3A and S3B). Taken together, the data indicate that RNAi against TEFs does not broadly activate stress responses involved in proteostasis.

Bottom Line: In contrast, when translation elongation is impaired, SKN-1 does not upregulate proteasome genes, and UPS activity is then reduced.SKN-1 therefore has a critical tissue-specific function in increasing proteasome gene expression and UPS activity under normal conditions, as well as when the UPS system is stressed, but mounts distinct responses when protein synthesis is perturbed.The data suggest that SKN-1 may increase longevity, not only through its well-documented role in boosting stress resistance, but also through contributing to protein homeostasis.

View Article: PubMed Central - PubMed

Affiliation: Joslin Diabetes Center, Harvard Stem Cell Institute, Harvard Medical School, Boston, Massachusetts, United States of America.

ABSTRACT
SKN-1, the Caenorhabditis elegans Nrf1/2/3 ortholog, promotes both oxidative stress resistance and longevity. SKN-1 responds to oxidative stress by upregulating genes that detoxify and defend against free radicals and other reactive molecules, a SKN-1/Nrf function that is both well-known and conserved. Here we show that SKN-1 has a broader and more complex role in maintaining cellular stress defenses. SKN-1 sustains expression and activity of the ubiquitin-proteasome system (UPS) and coordinates specific protective responses to perturbations in protein synthesis or degradation through the UPS. If translation initiation or elongation is impaired, SKN-1 upregulates overlapping sets of cytoprotective genes and increases stress resistance. When proteasome gene expression and activity are blocked, SKN-1 activates multiple classes of proteasome subunit genes in a compensatory response. SKN-1 thereby maintains UPS activity in the intestine in vivo under normal conditions and promotes survival when the proteasome is inhibited. In contrast, when translation elongation is impaired, SKN-1 does not upregulate proteasome genes, and UPS activity is then reduced. This indicates that UPS activity depends upon presence of an intact translation elongation apparatus; and it supports a model, suggested by genetic and biochemical studies in yeast, that protein synthesis and degradation may be coupled processes. SKN-1 therefore has a critical tissue-specific function in increasing proteasome gene expression and UPS activity under normal conditions, as well as when the UPS system is stressed, but mounts distinct responses when protein synthesis is perturbed. The specificity of these SKN-1-mediated stress responses, along with the apparent coordination between UPS and translation elongation activity, may promote protein homeostasis under stress or disease conditions. The data suggest that SKN-1 may increase longevity, not only through its well-documented role in boosting stress resistance, but also through contributing to protein homeostasis.

Show MeSH
Related in: MedlinePlus