Activation of the Unfolded Protein Response Is Required for Defenses against Bacterial Pore-Forming Toxin In Vivo

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.

Author Summary

Pore-forming toxins (PFTs) are bacterial toxins that form holes at the plasma membrane of cells and play an important role in the pathogenesis of many important human pathogens. Although PFTs comprise an important and the single largest class of bacterial protein virulence factors, how cells respond to these toxins has been understudied. We describe here the surprising discovery that a fundamental pathway of eukaryotic cell biology, the endoplasmic reticulum unfolded protein response (UPR), is activated by pore-forming toxins in Caenorhabditis elegans and mammalian cells. We find that this activation is functionally important since loss of either of two of the three arms of UPR leads to hypersensitivity of the nematode to attack by PFTs. The response of the UPR to PFTs can be separated from its response to unfolded proteins both at the level of activation and functional relevance. The response of the UPR to PFTs is dependent on a central pathway of cellular immunity, the p38 MAPK pathway. Our data show that the response of cells to bacterial attack can reveal unanticipated uses and connections between fundamental cell biological pathways.