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Activation of the unfolded protein response is required for defenses against bacterial pore-forming toxin in vivo.

Bischof LJ, Kao CY, Los FC, Gonzalez MR, Shen Z, Briggs SP, van der Goot FG, Aroian RV - PLoS Pathog. (2008)

Bottom Line: We find here that the UPR is one of the key downstream targets of the p38 MAPK pathway in response to PFT since loss of a functional p38 MAPK pathway leads to a failure of PFT to properly activate the ire-1-xbp-1 arm of the UPR.The UPR-mediated activation and response to PFTs is distinct from the canonical UPR-mediated response to unfolded proteins both in terms of its activation and functional sensitivities.These data demonstrate that the UPR, a fundamental intracellular pathway, can operate in intrinsic cellular defenses against bacterial attack.

View Article: PubMed Central - PubMed

Affiliation: Section of Cell and Developmental Biology, University of California, San Diego, La Jolla, California, United States of America.

ABSTRACT
Pore-forming toxins (PFTs) constitute the single largest class of proteinaceous bacterial virulence factors and are made by many of the most important bacterial pathogens. Host responses to these toxins are complex and poorly understood. We find that the endoplasmic reticulum unfolded protein response (UPR) is activated upon exposure to PFTs both in Caenorhabditis elegans and in mammalian cells. Activation of the UPR is protective in vivo against PFTs since animals that lack either the ire-1-xbp-1 or the atf-6 arms of the UPR are more sensitive to PFT than wild-type animals. The UPR acts directly in the cells targeted by the PFT. Loss of the UPR leads to a normal response against unrelated toxins or a pathogenic bacterium, indicating its PFT-protective role is specific. The p38 mitogen-activated protein (MAPK) kinase pathway has been previously shown to be important for cellular defenses against PFTs. We find here that the UPR is one of the key downstream targets of the p38 MAPK pathway in response to PFT since loss of a functional p38 MAPK pathway leads to a failure of PFT to properly activate the ire-1-xbp-1 arm of the UPR. The UPR-mediated activation and response to PFTs is distinct from the canonical UPR-mediated response to unfolded proteins both in terms of its activation and functional sensitivities. These data demonstrate that the UPR, a fundamental intracellular pathway, can operate in intrinsic cellular defenses against bacterial attack.

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The ER stress response mutants differ in their sensitivities to tunicamycin.A lethality assay was used to compare sensitivities of the ER stress mutants and wild-type N2 to tunicamycin. The percent of worms alive after 8 days of exposure to each concentration of tunicamycin was determined. Data are the mean and standard deviation of three independent experiments.
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ppat-1000176-g004: The ER stress response mutants differ in their sensitivities to tunicamycin.A lethality assay was used to compare sensitivities of the ER stress mutants and wild-type N2 to tunicamycin. The percent of worms alive after 8 days of exposure to each concentration of tunicamycin was determined. Data are the mean and standard deviation of three independent experiments.

Mentions: ER stress responses have been studied extensively for their role in protecting cells against unfolded proteins [10],[18]. One way to assess the role of the ER stress pathways in protecting against unfolded proteins is with the drug tunicamycin (a natural compound that leads to the accumulation of unfolded proteins in the ER due to its inhibitory effect on N-linked protein glycosylation [19]). Previous data in C. elegans have indicated different sensitivities of the three ER stress response pathways for tunicamycin [11],[12]. Using a different toxicity assay, we have confirmed these observations: atf-6(ok551) mutant animals have a similar sensitivity to tunicamycin as wild-type animals whereas both xbp-1(zc12) and pek-1(ok275) mutant animals are more readily killed by tunicamycin (Figure 4). These results are in contrast to the response of these different ER stress pathways to Cry5B, to which atf-6 mutant animals are more sensitive than pek-1 mutant animals. These data suggest that there are differences in how ER stress pathways are activated in response to unfolded proteins and to the PFT Cry5B.


Activation of the unfolded protein response is required for defenses against bacterial pore-forming toxin in vivo.

Bischof LJ, Kao CY, Los FC, Gonzalez MR, Shen Z, Briggs SP, van der Goot FG, Aroian RV - PLoS Pathog. (2008)

The ER stress response mutants differ in their sensitivities to tunicamycin.A lethality assay was used to compare sensitivities of the ER stress mutants and wild-type N2 to tunicamycin. The percent of worms alive after 8 days of exposure to each concentration of tunicamycin was determined. Data are the mean and standard deviation of three independent experiments.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2553261&req=5

ppat-1000176-g004: The ER stress response mutants differ in their sensitivities to tunicamycin.A lethality assay was used to compare sensitivities of the ER stress mutants and wild-type N2 to tunicamycin. The percent of worms alive after 8 days of exposure to each concentration of tunicamycin was determined. Data are the mean and standard deviation of three independent experiments.
Mentions: ER stress responses have been studied extensively for their role in protecting cells against unfolded proteins [10],[18]. One way to assess the role of the ER stress pathways in protecting against unfolded proteins is with the drug tunicamycin (a natural compound that leads to the accumulation of unfolded proteins in the ER due to its inhibitory effect on N-linked protein glycosylation [19]). Previous data in C. elegans have indicated different sensitivities of the three ER stress response pathways for tunicamycin [11],[12]. Using a different toxicity assay, we have confirmed these observations: atf-6(ok551) mutant animals have a similar sensitivity to tunicamycin as wild-type animals whereas both xbp-1(zc12) and pek-1(ok275) mutant animals are more readily killed by tunicamycin (Figure 4). These results are in contrast to the response of these different ER stress pathways to Cry5B, to which atf-6 mutant animals are more sensitive than pek-1 mutant animals. These data suggest that there are differences in how ER stress pathways are activated in response to unfolded proteins and to the PFT Cry5B.

Bottom Line: We find here that the UPR is one of the key downstream targets of the p38 MAPK pathway in response to PFT since loss of a functional p38 MAPK pathway leads to a failure of PFT to properly activate the ire-1-xbp-1 arm of the UPR.The UPR-mediated activation and response to PFTs is distinct from the canonical UPR-mediated response to unfolded proteins both in terms of its activation and functional sensitivities.These data demonstrate that the UPR, a fundamental intracellular pathway, can operate in intrinsic cellular defenses against bacterial attack.

View Article: PubMed Central - PubMed

Affiliation: Section of Cell and Developmental Biology, University of California, San Diego, La Jolla, California, United States of America.

ABSTRACT
Pore-forming toxins (PFTs) constitute the single largest class of proteinaceous bacterial virulence factors and are made by many of the most important bacterial pathogens. Host responses to these toxins are complex and poorly understood. We find that the endoplasmic reticulum unfolded protein response (UPR) is activated upon exposure to PFTs both in Caenorhabditis elegans and in mammalian cells. Activation of the UPR is protective in vivo against PFTs since animals that lack either the ire-1-xbp-1 or the atf-6 arms of the UPR are more sensitive to PFT than wild-type animals. The UPR acts directly in the cells targeted by the PFT. Loss of the UPR leads to a normal response against unrelated toxins or a pathogenic bacterium, indicating its PFT-protective role is specific. The p38 mitogen-activated protein (MAPK) kinase pathway has been previously shown to be important for cellular defenses against PFTs. We find here that the UPR is one of the key downstream targets of the p38 MAPK pathway in response to PFT since loss of a functional p38 MAPK pathway leads to a failure of PFT to properly activate the ire-1-xbp-1 arm of the UPR. The UPR-mediated activation and response to PFTs is distinct from the canonical UPR-mediated response to unfolded proteins both in terms of its activation and functional sensitivities. These data demonstrate that the UPR, a fundamental intracellular pathway, can operate in intrinsic cellular defenses against bacterial attack.

Show MeSH
Related in: MedlinePlus