XBP-1 regulates signal transduction, transcription factors and bone marrow colonization in B cells.
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.
Hu
Chih-Chi Andrew
CC
Department of Biology, Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, MA 02142, USA.
Dougan
Stephanie K
SK
McGehee
Annette M
AM
Love
J Christopher
JC
Ploegh
Hidde L
HL
D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000502:physiology*; D001853:Bone Marrow / Q000502:physiology*; D002454:Cell Differentiation; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D000071701:Regulatory Factor X Transcription Factors; D015398:Signal Transduction; D014157:Transcription Factors / Q000096:biosynthesis* / Q000172:deficiency / Q000502:physiology; D000071717:X-Box Binding Protein 1
D004268:DNA-Binding Proteins; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605544:Xbp1 protein, mouse