An essential role for XBP-1 in host protection against immune activation in C. elegans
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 IR...
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| Format: | Article |
| Language: | en_US |
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Nature Publishing Group
2011
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| Online Access: | http://hdl.handle.net/1721.1/66544 https://orcid.org/0000-0002-4109-5152 |
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| author | Richardson, Claire Elissa Kooistra, Tristan G. Kim, Dennis H. |
| author2 | Whitaker College of Health Sciences and Technology |
| author_facet | Whitaker College of Health Sciences and Technology Richardson, Claire Elissa Kooistra, Tristan G. Kim, Dennis H. |
| author_sort | Richardson, Claire Elissa |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T16:09:18Z |
| format | Article |
| id | mit-1721.1/66544 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T16:09:18Z |
| publishDate | 2011 |
| publisher | Nature Publishing Group |
| record_format | dspace |
| spelling | mit-1721.1/665442022-09-29T18:35:13Z An essential role for XBP-1 in host protection against immune activation in C. elegans Richardson, Claire Elissa Kooistra, Tristan G. Kim, Dennis H. Whitaker College of Health Sciences and Technology Massachusetts Institute of Technology. Department of Biology Kim, Dennis H. Kim, Dennis H. Richardson, Claire Elissa Kooistra, Tristan G. 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. Howard Hughes Medical Institute (Summer Research Fellowship) National Institutes of Health (U.S.) (NIH grant R01-GM084477) Burroughs Wellcome Fund (Career Award in the Biomedical Sciences) Ellison Medical Foundation (New Scholar Award) 2011-10-24T13:53:49Z 2011-10-24T13:53:49Z 2010-02 2009-06 Article http://purl.org/eprint/type/JournalArticle 1476-4687 0028-0836 http://hdl.handle.net/1721.1/66544 Richardson, Claire E., Tristan Kooistra, and Dennis H. Kim. “An essential role for XBP-1 in host protection against immune activation in C. elegans.” Nature 463 (2010): 1092-1095. https://orcid.org/0000-0002-4109-5152 en_US http://dx.doi.org/10.1038/nature08762 Nature Creative Commons Attribution-Noncommercial-Share Alike 3.0 http://creativecommons.org/licenses/by-nc-sa/3.0/ application/pdf Nature Publishing Group Kim |
| spellingShingle | Richardson, Claire Elissa Kooistra, Tristan G. Kim, Dennis H. An essential role for XBP-1 in host protection against immune activation in C. elegans |
| title | An essential role for XBP-1 in host protection against immune activation in C. elegans |
| title_full | An essential role for XBP-1 in host protection against immune activation in C. elegans |
| title_fullStr | An essential role for XBP-1 in host protection against immune activation in C. elegans |
| title_full_unstemmed | An essential role for XBP-1 in host protection against immune activation in C. elegans |
| title_short | An essential role for XBP-1 in host protection against immune activation in C. elegans |
| title_sort | essential role for xbp 1 in host protection against immune activation in c elegans |
| url | http://hdl.handle.net/1721.1/66544 https://orcid.org/0000-0002-4109-5152 |
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