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Plasma cell differentiation and the unfolded protein response intersect at the transcription factor XBP-1

Nature Immunology volume 4, pages 321–329 (2003)Cite this article

30 January 2024 Editor's Note: Readers are alerted that concerns have been raised regarding the figures in this article. These concerns are being investigated and appropriate editorial action will be taken once this matter is resolved.

An Author Correction to this article was published on 10 April 2024

This article has been updated

Abstract

The transcription factor X-box binding protein 1 (XBP-1) is essential for the differentiation of plasma cells and the unfolded protein response (UPR). Here we show that UPR-induced splicing of XBP-1 by the transmembrane endonuclease IRE1 is required to restore production of immunoglobulin in XBP-1−/− mouse B cells, providing an integral link between XBP-1, the UPR and plasma cell differentiation. Signals involved in plasma cell differentiation, specifically interleukin-4, control the transcription of XBP-1, whereas its post-transcriptional processing is dependent on synthesis of immunoglobulins during B cell differentiation. We also show that XBP-1 is involved in controlling the production of interleukin-6, a cytokine that is essential for plasma cell survival. Thus, signals upstream and downstream of XBP-1 integrate plasma cell differentiation with the UPR.

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Figure 1: Induction of Xbp1 mRNA in naive B cells by IL-4.
Figure 2: IRE1-mediated splicing of Xbp1 during plasma cell differentiation.
Figure 3: Xbp1 splicing and the UPR in BCL1 terminal differentiation.
Figure 4: Production of spliced XBP-1 depends on the IgM heavy chain.
Figure 5: Ectopic expression of spliced XBP-1 enhances IgM secretion.
Figure 6: Spliced XBP-1 restores Ig production in XBP-1−/− B cells.
Figure 7: Spliced XBP-1 induces IL-6.

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Change history

  • 30 January 2024

    Editor's Note: Readers are alerted that concerns have been raised regarding the figures in this article. These concerns are being investigated and appropriate editorial action will be taken once this matter is resolved.

  • 10 April 2024

    A Correction to this paper has been published: https://doi.org/10.1038/s41590-024-01827-8

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Acknowledgements

We thank M. Grusby, K. Mowen, M. Oukka, S. Szabo and A. Wurster for reviewing the manuscript; K. Sigrist for producing the XBP-1-RAG chimeras; and C. McCall for preparing the manuscript. This work was supported by grants from the National Institutes of Health (L.H.G.) and a gift of the G. Harold and Leila Y. Mathers Charitable Foundation (L.H.G.). K.R. is supported by grants from the US National Institutes of Health (NIH) and by the Volkswagen Foundation. N.N.I. is supported by a fellowship from the Irvington Institute. K.L.O is supported by an NIH grant.

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Author notes

  1. Neal N. Iwakoshi and Ann-Hwee Lee: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Immunology and Infectious Diseases, Harvard School of Public Health 651 Huntington Avenue, Boston, 02115-6017, Massachusetts, USA

    Neal N. Iwakoshi, Ann-Hwee Lee, Prasanth Vallabhajosyula & Laurie H. Glimcher

  2. Center for Blood Research, Harvard Medical School, Boston, 02115, Massachusetts, USA

    Kevin L. Otipoby & Klaus Rajewsky

  3. Department of Medicine, Harvard Medical School, Boston, 02115, Massachusetts, USA

    Laurie H. Glimcher

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Correspondence to Laurie H. Glimcher.

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Iwakoshi, N., Lee, AH., Vallabhajosyula, P. et al. Plasma cell differentiation and the unfolded protein response intersect at the transcription factor XBP-1. Nat Immunol 4, 321–329 (2003). https://doi.org/10.1038/ni907

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