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

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  • Marcella Calfon

    (Skirball Institute of Biomolecular Medicine, New York University School of Medicine)

  • Huiqing Zeng

    (Skirball Institute of Biomolecular Medicine, New York University School of Medicine)

  • Fumihiko Urano

    (Skirball Institute of Biomolecular Medicine, New York University School of Medicine)

  • Jeffery H. Till

    (Skirball Institute of Biomolecular Medicine, New York University School of Medicine)

  • Stevan R. Hubbard

    (Skirball Institute of Biomolecular Medicine, New York University School of Medicine)

  • Heather P. Harding

    (Skirball Institute of Biomolecular Medicine, New York University School of Medicine)

  • Scott G. Clark

    (Skirball Institute of Biomolecular Medicine, New York University School of Medicine)

  • David Ron

    (Skirball Institute of Biomolecular Medicine, New York University School of Medicine)

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.

Suggested Citation

  • Marcella Calfon & Huiqing Zeng & Fumihiko Urano & Jeffery H. Till & Stevan R. Hubbard & Heather P. Harding & Scott G. Clark & David Ron, 2002. "IRE1 couples endoplasmic reticulum load to secretory capacity by processing the XBP-1 mRNA," Nature, Nature, vol. 415(6867), pages 92-96, January.
  • Handle: RePEc:nat:nature:v:415:y:2002:i:6867:d:10.1038_415092a
    DOI: 10.1038/415092a
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    Cited by:

    1. Kazuhiro Kashiwagi & Yuichi Shichino & Tatsuya Osaki & Ayako Sakamoto & Madoka Nishimoto & Mari Takahashi & Mari Mito & Friedemann Weber & Yoshiho Ikeuchi & Shintaro Iwasaki & Takuhiro Ito, 2021. "eIF2B-capturing viral protein NSs suppresses the integrated stress response," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
    2. Dadi Jiang & Youming Guo & Tianyu Wang & Liang Wang & Yuelong Yan & Ling Xia & Rakesh Bam & Zhifen Yang & Hyemin Lee & Takao Iwawaki & Boyi Gan & Albert C. Koong, 2024. "IRE1α determines ferroptosis sensitivity through regulation of glutathione synthesis," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    3. Vladimir Potapov & Jenifer B Kaplan & Amy E Keating, 2015. "Data-Driven Prediction and Design of bZIP Coiled-Coil Interactions," PLOS Computational Biology, Public Library of Science, vol. 11(2), pages 1-28, February.
    4. Fiamma Salerno & Andrew J. M. Howden & Louise S. Matheson & Özge Gizlenci & Michael Screen & Holger Lingel & Monika C. Brunner-Weinzierl & Martin Turner, 2023. "An integrated proteome and transcriptome of B cell maturation defines poised activation states of transitional and mature B cells," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    5. Jean-Claude Garaud & Jean-Nicolas Schickel & Gilles Blaison & Anne-Marie Knapp & Doulaye Dembele & Julie Ruer-Laventie & Anne-Sophie Korganow & Thierry Martin & Pauline Soulas-Sprauel & Jean-Louis Pas, 2011. "B Cell Signature during Inactive Systemic Lupus Is Heterogeneous: Toward a Biological Dissection of Lupus," PLOS ONE, Public Library of Science, vol. 6(8), pages 1-9, August.
    6. Rashmi Tripathi & Nathalie Benz & Bridget Culleton & Pascal Trouvé & Claude Férec, 2014. "Biophysical Characterisation of Calumenin as a Charged F508del-CFTR Folding Modulator," PLOS ONE, Public Library of Science, vol. 9(8), pages 1-15, August.
    7. Fátima Cairrão & Cristiana C. Santos & Adrien Thomas & Scot Marsters & Avi Ashkenazi & Pedro M. Domingos, 2022. "Pumilio protects Xbp1 mRNA from regulated Ire1-dependent decay," Nature Communications, Nature, vol. 13(1), pages 1-13, December.

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