Limits...
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.

Show MeSH

Related in: MedlinePlus

TEF knockdown increases oxidative stress resistance.(A) Increased TBHP resistance after TEF RNAi. In (A–C), data were analyzed by JMP and plotted with EXCEL. Representative experiments are shown, with replicates, statistics, and percent changes in survival time provided in Table S2 (A), Table S3 (B), and Table S4 (C). Error bars represent the SEM, and P values were calculated by log-rank. *P<0.0001. (B) skn-1 contributes to TBHP resistance deriving from TEF RNAi. (C) Resistance to Arsenite resulting from TEF RNAi. (D) Lifespan analysis of worms fed TEFs or TIF (ifg-1) RNAi bacteria. A composite of three replicates (Table S5A) is shown.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3111486&req=5

pgen-1002119-g003: TEF knockdown increases oxidative stress resistance.(A) Increased TBHP resistance after TEF RNAi. In (A–C), data were analyzed by JMP and plotted with EXCEL. Representative experiments are shown, with replicates, statistics, and percent changes in survival time provided in Table S2 (A), Table S3 (B), and Table S4 (C). Error bars represent the SEM, and P values were calculated by log-rank. *P<0.0001. (B) skn-1 contributes to TBHP resistance deriving from TEF RNAi. (C) Resistance to Arsenite resulting from TEF RNAi. (D) Lifespan analysis of worms fed TEFs or TIF (ifg-1) RNAi bacteria. A composite of three replicates (Table S5A) is shown.

Mentions: RNAi against TIF or ribosomal protein genes increases resistance to various environmental stresses [23], [34]–[36]. We therefore examined whether TEF knockdown affects resistance to two different sources of oxidative stress, the organic hydroperoxide tert-butyl hydrogen peroxide (TBHP), and the metalloid sodium arsenite (As) [20]. TBHP resistance was dramatically increased after knockdown of multiple TEFs in wild type animals (Figure 3A; Table S2). In contrast, RNAi against eef-2 or eef-1G did not robustly increase oxidative stress resistance in skn-1(zu135) mutants, indicating that skn-1 is essential for the TBHP resistance that derives from TEF knockdown (Figure 3B; Table S3). TEF inhibition also increased resistance to As (Figure 3C; Table S4). We conclude that the SKN-1-mediated transcriptional response to impaired translation elongation increases oxidative stress resistance.


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 knockdown increases oxidative stress resistance.(A) Increased TBHP resistance after TEF RNAi. In (A–C), data were analyzed by JMP and plotted with EXCEL. Representative experiments are shown, with replicates, statistics, and percent changes in survival time provided in Table S2 (A), Table S3 (B), and Table S4 (C). Error bars represent the SEM, and P values were calculated by log-rank. *P<0.0001. (B) skn-1 contributes to TBHP resistance deriving from TEF RNAi. (C) Resistance to Arsenite resulting from TEF RNAi. (D) Lifespan analysis of worms fed TEFs or TIF (ifg-1) RNAi bacteria. A composite of three replicates (Table S5A) is shown.
© Copyright Policy
Related In: Results  -  Collection

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

pgen-1002119-g003: TEF knockdown increases oxidative stress resistance.(A) Increased TBHP resistance after TEF RNAi. In (A–C), data were analyzed by JMP and plotted with EXCEL. Representative experiments are shown, with replicates, statistics, and percent changes in survival time provided in Table S2 (A), Table S3 (B), and Table S4 (C). Error bars represent the SEM, and P values were calculated by log-rank. *P<0.0001. (B) skn-1 contributes to TBHP resistance deriving from TEF RNAi. (C) Resistance to Arsenite resulting from TEF RNAi. (D) Lifespan analysis of worms fed TEFs or TIF (ifg-1) RNAi bacteria. A composite of three replicates (Table S5A) is shown.
Mentions: RNAi against TIF or ribosomal protein genes increases resistance to various environmental stresses [23], [34]–[36]. We therefore examined whether TEF knockdown affects resistance to two different sources of oxidative stress, the organic hydroperoxide tert-butyl hydrogen peroxide (TBHP), and the metalloid sodium arsenite (As) [20]. TBHP resistance was dramatically increased after knockdown of multiple TEFs in wild type animals (Figure 3A; Table S2). In contrast, RNAi against eef-2 or eef-1G did not robustly increase oxidative stress resistance in skn-1(zu135) mutants, indicating that skn-1 is essential for the TBHP resistance that derives from TEF knockdown (Figure 3B; Table S3). TEF inhibition also increased resistance to As (Figure 3C; Table S4). We conclude that the SKN-1-mediated transcriptional response to impaired translation elongation increases oxidative stress resistance.

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