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

Abstract

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 disease1. The IRE1–XBP1/Hac1 pathway is a major branch of the UPR that has been conserved from yeast to human2,3,4,5,6. X-box binding protein 1 (XBP1) is required for the differentiation of the highly secretory plasma cells of the mammalian adaptive immune system7,8, but recent work also points to reciprocal interactions between the UPR and other aspects of immunity and inflammation9,10,11. 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 pathogens12. 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.

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Figure 1: PMK-1 p38 MAPK-dependent activation of the IRE-1–XBP-1-dependent UPR by P. aeruginosa infection.
Figure 2: XBP-1 is required for C. elegans development and survival on P. aeruginosa.
Figure 3: Suppression of the P. aeruginosa -induced larval lethality phenotype of xbp-1(zc12) by pmk-1(km25).
Figure 4: XBP-1 is required for development and survival during pathogen-independent constitutive activation of PMK-1.

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Acknowledgements

Electron microscopy was performed by M. McKee in the Microscopy Core of the Center for Systems Biology/Program in Membrane Biology at Massachusetts General Hospital (supported by NIH grants DK43351 and DK57521). We thank E. Hartwieg and G. Voeltz for discussions regarding the interpretation of electron microscopy images. We thank T. Stiernagle and the Caenorhabditis Genetics Center (supported by the NIH), and S. Mitani and the National Bioresource Project of Japan for strains. T.K. was supported by summer research fellowships from the Howard Hughes Medical Institute. This work was supported by NIH grant R01-GM084477, a Career Award in the Biomedical Sciences from the Burroughs Wellcome Fund, and an Ellison Medical Foundation New Scholar Award (to D.H.K.).

Author Contributions C.E.R. and D.H.K. conceived and planned experiments. C.E.R. and T.K. performed experiments. C.E.R. and D.H.K. analysed the data and wrote the paper.

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Correspondence to Dennis H. Kim.

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Richardson, C., Kooistra, T. & Kim, D. An essential role for XBP-1 in host protection against immune activation in C. elegans. Nature 463, 1092–1095 (2010). https://doi.org/10.1038/nature08762

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