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IRE1 couples endoplasmic reticulum load to secretory capacity by processing the XBP-1 mRNA

Nature volume 415, pages 92–96 (2002)Cite this article

A Corrigendum to this article was published on 14 November 2002

Abstract

The unfolded protein response (UPR), caused by stress, matches the folding capacity of endoplasmic reticulum (ER) to the load of client proteins in the organelle1,2. In yeast, processing of HAC1 mRNA by activated Ire1 leads to synthesis of the transcription factor Hac1 and activation of the UPR3. The responses to activated IRE1 in metazoans are less well understood. Here we demonstrate that mutations in either ire-1 or the transcription-factor-encoding xbp-1 gene abolished the UPR in Caenorhabditis elegans. Mammalian XBP-1 is essential for immunoglobulin secretion and development of plasma cells4, and high levels of XBP-1 messenger RNA are found in specialized secretory cells5. Activation of the UPR causes IRE1-dependent splicing of a small intron from the XBP-1 mRNA both in C. elegans and mice. The protein encoded by the processed murine XBP-1 mRNA accumulated during the UPR, whereas the protein encoded by unprocessed mRNA did not. Purified mouse IRE1 accurately cleaved XBP-1 mRNA in vitro, indicating that XBP-1 mRNA is a direct target of IRE1 endonucleolytic activity. Our findings suggest that physiological ER load regulates a developmental decision in higher eukaryotes.

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Figure 1: Identifying mutants in the C. elegans UPR.
Figure 2: Mammalian XBP-1 expression during ER stress is dependent on IRE1.
Figure 3: IRE1-mediated processing of XBP-1 mRNA.
Figure 4: Processing of XBP-1 mRNA controls expression of the encoded protein.

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Acknowledgements

We thank C. Chiu for help in initiating the nematode work; A. Bertolotti, D. Levy and E. Y. Skolnik for useful discussions; Y. Kohara for C. elegans EST clones; and A. Ron and R. Onn for calculating the synthesis rate of XBP1 proteins. This work was supported by grants from the National Institutes of Health. D.R. is a Scholar of the Ellison Medical Foundation.

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  1. Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, 10016, New York, USA

    Marcella Calfon, Huiqing Zeng, Fumihiko Urano, Jeffery H. Till, Stevan R. Hubbard, Heather P. Harding, Scott G. Clark & David Ron

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Calfon, M., Zeng, H., Urano, F. et al. IRE1 couples endoplasmic reticulum load to secretory capacity by processing the XBP-1 mRNA. Nature 415, 92–96 (2002). https://doi.org/10.1038/415092a

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