XBP-1 regulates signal transduction, transcription factors and bone marrow colonization in B cells

Chih Chi Andrew Hu, Stephanie K. Dougan, Annette M. McGehee, J. Christopher Love, Hidde L. Ploegh

Research output: Contribution to journalArticle

127 Scopus citations

Abstract

XBP-1, a transcription factor that drives the unfolded protein response (UPR), is activated in B cells when they differentiate to plasma cells. Here, we show that in the B cells, whose capacity to secrete IgM has been eliminated, XBP-1 is induced normally on induction of differentiation, suggesting that activation of XBP-1 in B cells is a differentiation-dependent event, but not the result of a UPR caused by the abundant synthesis of secreted IgM. Without XBP-1, B cells fail to signal effectively through the B-cell receptor. The signalling defects lead to aberrant expression of the plasma cell transcription factors IRF4 and Blimp-1, and altered levels of activation-induced cytidine deaminase and sphingosine-1-phosphate receptor. Using XBP-1-deficient/Blimp-1- GFP transgenic mice, we find that XBP-1-deficient B cells form antibody-secreting plasmablasts in response to initial immunization; however, these plasmablasts respond ineffectively to CXCl12. They fail to colonize the bone marrow and do not sustain antibody production. These findings define the role of XBP-1 in normal plasma cell development and have implications for management of B-cell malignancies.

Original languageEnglish (US)
Pages (from-to)1624-1636
Number of pages13
JournalEMBO Journal
Volume28
Issue number11
DOIs
StatePublished - Jun 3 2009

Keywords

  • BCR signalling
  • Blimp-1
  • Chemokine receptors
  • CXCl12
  • IRF4

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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