Journal Article

An essential role for XBP-1 in host protection against immune activation in C. elegans

Kooistra, Tristan, Richardson, Claire E., Kim, Dennis H.

2010

Overview

XBP-1 a host defence from innate immunity The unfolded protein response (UPR), a signalling pathway activated by the accumulation of unfolded proteins in the endoplasmic reticulum, is known to contribute to the defence against infectious agents and toxins. Here it is shown that activation of innate immunity in Caenorhabditis elegans induces the UPR mediated by X-box binding protein 1 (XBP-1). This points to an ancient, conserved role for the XBP-1-dependent UPR in protecting cells against the endoplasmic reticulum stress generated from an immune response. The unfolded protein response, known to contribute to the defence against infectious agents and toxins, is shown here to protect Caenorhabditis elegans larvae against detrimental effects of the innate immune response to infection with Pseudomonas aeruginosa . The findings establish innate immunity as a physiologically relevant inducer of ER stress during C. elegans development. The detection and compensatory response to the accumulation of unfolded proteins in the endoplasmic reticulum (ER), termed the unfolded protein response (UPR), represents a conserved cellular homeostatic mechanism with important roles in normal development and in the pathogenesis of disease 1 . The IRE1–XBP1/Hac1 pathway is a major branch of the UPR that has been conserved from yeast to human 2 , 3 , 4 , 5 , 6 . X-box binding protein 1 (XBP1) is required for the differentiation of the highly secretory plasma cells of the mammalian adaptive immune system 7 , 8 , but recent work also points to reciprocal interactions between the UPR and other aspects of immunity and inflammation 9 , 10 , 11 . We have been studying innate immunity in the nematode Caenorhabditis elegans , having established a principal role for a conserved PMK-1 p38 mitogen-activated protein kinase (MAPK) pathway in mediating resistance to microbial pathogens 12 . Here we show that during C. elegans development, XBP-1 has an essential role in protecting the host during activation of innate immunity. Activation of the PMK-1-mediated response to infection with Pseudomonas aeruginosa induces the XBP-1-dependent UPR. Whereas a loss-of-function xbp-1 mutant develops normally in the presence of relatively non-pathogenic bacteria, infection of the xbp-1 mutant with P. aeruginosa leads to disruption of ER morphology and larval lethality. Unexpectedly, the larval lethality phenotype on pathogenic P. aeruginosa is suppressed by loss of PMK-1-mediated immunity. Furthermore, hyperactivation of PMK-1 causes larval lethality in the xbp-1 mutant even in the absence of pathogenic bacteria. Our data establish innate immunity as a physiologically relevant inducer of ER stress during C. elegans development and indicate that an ancient, conserved role for XBP-1 may be to protect the host organism from the detrimental effects of mounting an innate immune response to microbes.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/136/334/1582/712 / 631/250/255/1318 / 631/250/262 / 631/250/516 / Animals / Bacteriology / Biological and medical sciences / Caenorhabditis elegans / Caenorhabditis elegans - growth & development / Caenorhabditis elegans - immunology / Caenorhabditis elegans - microbiology / Caenorhabditis elegans Proteins - genetics / Caenorhabditis elegans Proteins - immunology / Caenorhabditis elegans Proteins - metabolism / Carrier Proteins - genetics / Carrier Proteins - immunology / Carrier Proteins - metabolism / E coli / Endoplasmic reticulum / Endoplasmic Reticulum - immunology / Endoplasmic Reticulum - metabolism / Endoplasmic Reticulum - pathology / Enzyme Activation / Fundamental and applied biological sciences. Psychology / Genes / Genes, Essential / Genetic aspects / Humanities and Social Sciences / Humans / Immune response / Immune system / Immunity, Innate - immunology / Larva - growth & development / Larva - immunology / Larva - microbiology / letter / Microbiology / Mitogen-Activated Protein Kinases - immunology / Mitogen-Activated Protein Kinases - metabolism / Molecular and cellular biology / multidisciplinary / Mutation - genetics / Mycology / Nematoda / Pathogenicity, host-agent relations, miscellaneous strains, epidemiology / Phenotype / Physiological aspects / Protein folding / Protein Serine-Threonine Kinases - metabolism / Proteins / Pseudomonas aeruginosa / Pseudomonas aeruginosa - immunology / Pseudomonas aeruginosa - pathogenicity / Pseudomonas aeruginosa - physiology / Science / Science (multidisciplinary) / Survival Analysis / Unfolded Protein Response - immunology / Unfolded Protein Response - physiology / Yeasts