activation of the unfolded protein response is required for defenses against bacterial pore-forming toxin in vivo需要展开的蛋白质反应的激活防御细菌造孔毒素在体内.pdfVIP

Activation of the Unfolded Protein Response Is Required for Defenses against Bacterial Pore-Forming Toxin In Vivo 1¤ 1 1 2 1 Larry J. Bischof , Cheng-Yuan Kao , Ferdinand C. O. Los , Manuel R. Gonzalez , Zhouxin Shen , 1 2 1 Steven P. Briggs , F. Gisou van der Goot , Raffi V. Aroian * 1 Section of Cell and Developmental Biology, University of California, San Diego, La Jolla, California, United States of America, 2 Global Health Institute, Ecole ´ ´ Polytechnique Federale de Lausanne, Lausanne, Switzerland 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