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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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Specific SKN-1–mediated responses to impaired protein synthesis and degradation.SKN-1 target genes are activated through distinct mechanisms by interference with translation initiation or elongation, so that TEF RNAi (red) induces a more restricted set of SKN-1 target genes than TIF RNAi (blue). TEF RNAi also impairs UPS activity, supporting the idea that proteasome activity and translation elongation are mechanistically coupled processes. In the intestine, SKN-1 is also important for the “bounce-back” response to proteasome inhibition, and for UPS activity under normal conditions (green).
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pgen-1002119-g006: Specific SKN-1–mediated responses to impaired protein synthesis and degradation.SKN-1 target genes are activated through distinct mechanisms by interference with translation initiation or elongation, so that TEF RNAi (red) induces a more restricted set of SKN-1 target genes than TIF RNAi (blue). TEF RNAi also impairs UPS activity, supporting the idea that proteasome activity and translation elongation are mechanistically coupled processes. In the intestine, SKN-1 is also important for the “bounce-back” response to proteasome inhibition, and for UPS activity under normal conditions (green).

Mentions: We have determined that interference with either mRNA translation or proteasome integrity results in induction of SKN-1-mediated stress responses. These responses are remarkably specific, in that SKN-1 upregulates distinct suites of target genes in response to impairment of translation initiation, translation elongation, or proteasome activity (Figure 6). When protein synthesis is inhibited, SKN-1 increases oxidative stress resistance. If proteasome subunit expression is blocked, SKN-1 attempts to compensate by upregulating proteasome genes in multiple tissues. In contrast, proteasome gene expression is not increased when translation is impaired, and proteasome activity is actually decreased in response to reduced translation elongation, suggesting that the specificity of these SKN-1-mediated functions may be important for maintaining protein homeostasis.


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)

Specific SKN-1–mediated responses to impaired protein synthesis and degradation.SKN-1 target genes are activated through distinct mechanisms by interference with translation initiation or elongation, so that TEF RNAi (red) induces a more restricted set of SKN-1 target genes than TIF RNAi (blue). TEF RNAi also impairs UPS activity, supporting the idea that proteasome activity and translation elongation are mechanistically coupled processes. In the intestine, SKN-1 is also important for the “bounce-back” response to proteasome inhibition, and for UPS activity under normal conditions (green).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3111486&req=5

pgen-1002119-g006: Specific SKN-1–mediated responses to impaired protein synthesis and degradation.SKN-1 target genes are activated through distinct mechanisms by interference with translation initiation or elongation, so that TEF RNAi (red) induces a more restricted set of SKN-1 target genes than TIF RNAi (blue). TEF RNAi also impairs UPS activity, supporting the idea that proteasome activity and translation elongation are mechanistically coupled processes. In the intestine, SKN-1 is also important for the “bounce-back” response to proteasome inhibition, and for UPS activity under normal conditions (green).
Mentions: We have determined that interference with either mRNA translation or proteasome integrity results in induction of SKN-1-mediated stress responses. These responses are remarkably specific, in that SKN-1 upregulates distinct suites of target genes in response to impairment of translation initiation, translation elongation, or proteasome activity (Figure 6). When protein synthesis is inhibited, SKN-1 increases oxidative stress resistance. If proteasome subunit expression is blocked, SKN-1 attempts to compensate by upregulating proteasome genes in multiple tissues. In contrast, proteasome gene expression is not increased when translation is impaired, and proteasome activity is actually decreased in response to reduced translation elongation, suggesting that the specificity of these SKN-1-mediated functions may be important for maintaining protein homeostasis.

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