Limits...
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.

Show MeSH

Related in: MedlinePlus

Schematic illustrating relationship between p38 MAPK, ire-1-xbp-1, and PFT defense pathways.PFTs at the cell surface of epithelial cells activate p38 MAPK that activates IRE-1 that induces splicing of xbp-1, which then turns on defense against PFTs. Residual activation of xbp-1 targets in the absence of the p38 MAPK pathway suggests there might be p38-independent activation of the ire-1-xbp-1 pathway in response to PFT as well (not shown). Independent of IRE-1 activation, p38 MAPK can also activate TTM-2 and other PFT defenses. Tunicamycin, which causes the accumulation of unfolded proteins in the ER, activates IRE-1 via a mechanism independent of the PFT and p38 MAPK.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2553261&req=5

ppat-1000176-g006: Schematic illustrating relationship between p38 MAPK, ire-1-xbp-1, and PFT defense pathways.PFTs at the cell surface of epithelial cells activate p38 MAPK that activates IRE-1 that induces splicing of xbp-1, which then turns on defense against PFTs. Residual activation of xbp-1 targets in the absence of the p38 MAPK pathway suggests there might be p38-independent activation of the ire-1-xbp-1 pathway in response to PFT as well (not shown). Independent of IRE-1 activation, p38 MAPK can also activate TTM-2 and other PFT defenses. Tunicamycin, which causes the accumulation of unfolded proteins in the ER, activates IRE-1 via a mechanism independent of the PFT and p38 MAPK.

Mentions: A link between the p38 and UPR pathways has been shown in previous studies, although not with the level of functional relevance demonstrated here. Various arms of the UPR have been shown as both upstream or downstream of the p38 pathway, depending on the circumstances [25],[26],[27],[28],[29],[30]. The p38 pathway itself is implicated extensively in innate immune protection of many organisms against pathogens [31] and against PFTs in worms and mammals [6],[7]. Our data presented here for the first time functionally link the UPR to this major innate immune signal transduction pathway. Our findings on the activation and role of the UPR and p38 pathways in defense against PFT are summarized in Figure 6.


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)

Schematic illustrating relationship between p38 MAPK, ire-1-xbp-1, and PFT defense pathways.PFTs at the cell surface of epithelial cells activate p38 MAPK that activates IRE-1 that induces splicing of xbp-1, which then turns on defense against PFTs. Residual activation of xbp-1 targets in the absence of the p38 MAPK pathway suggests there might be p38-independent activation of the ire-1-xbp-1 pathway in response to PFT as well (not shown). Independent of IRE-1 activation, p38 MAPK can also activate TTM-2 and other PFT defenses. Tunicamycin, which causes the accumulation of unfolded proteins in the ER, activates IRE-1 via a mechanism independent of the PFT and p38 MAPK.
© Copyright Policy
Related In: Results  -  Collection

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

ppat-1000176-g006: Schematic illustrating relationship between p38 MAPK, ire-1-xbp-1, and PFT defense pathways.PFTs at the cell surface of epithelial cells activate p38 MAPK that activates IRE-1 that induces splicing of xbp-1, which then turns on defense against PFTs. Residual activation of xbp-1 targets in the absence of the p38 MAPK pathway suggests there might be p38-independent activation of the ire-1-xbp-1 pathway in response to PFT as well (not shown). Independent of IRE-1 activation, p38 MAPK can also activate TTM-2 and other PFT defenses. Tunicamycin, which causes the accumulation of unfolded proteins in the ER, activates IRE-1 via a mechanism independent of the PFT and p38 MAPK.
Mentions: A link between the p38 and UPR pathways has been shown in previous studies, although not with the level of functional relevance demonstrated here. Various arms of the UPR have been shown as both upstream or downstream of the p38 pathway, depending on the circumstances [25],[26],[27],[28],[29],[30]. The p38 pathway itself is implicated extensively in innate immune protection of many organisms against pathogens [31] and against PFTs in worms and mammals [6],[7]. Our data presented here for the first time functionally link the UPR to this major innate immune signal transduction pathway. Our findings on the activation and role of the UPR and p38 pathways in defense against PFT are summarized in Figure 6.

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