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

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.

Membrane lipid saturation activates endoplasmic reticulum unfolded protein response transducers through their transmembrane domains

“…By stabilizing the dimer, an increase in the acyl chain saturation could lower the threshold of luminal stress required for unfolded protein-dependent activation of IRE1α and PERK, and levels of unfolded protein stress could modulate the response to lipids by a similar cooperative mechanism. Lipid sensing by IRE1 and PERK may account for instances, such as B-cell development, marked by an apparent discrepancy between a modest level of unfolded protein load and substantial UPR signaling (33)(34)(35). It may therefore be interesting to examine the potential role of lipids as instigators of what has been termed an anticipatory UPR (36, 37).…”

Re-thinking the functions of IgA+plasma cells

“…44 Moreover, PC survival factors are directly induced by XBP-1s including IL-6 37 and iNOS, 45 and nitric oxide (NO), the byproduct of iNOS activity, has also been described to have anti-apoptotic effects in different cell subsets. 46,47 Recently, it was shown that iNOS deficiency in PC leads to a decrease in both viability and an increase in caspase 3 activation, under conditions of polyclonal B cell stimulation in vitro and in vivo.…”

“…52 PC migrate to the BM by up-regulating CXCR4 in order to respond to CXCL12 which is expressed in the medullary cords of LN and in the BM. 53 Interestingly, XBP-1 has been implicated in PC migration toward CXCL12, 44 suggesting that acquisition of CXCL12 responsiveness through the chemokine receptor CXCR4 is part of the PC differentiation program. Within the BM niche itself, particular cytokines are very important for sustaining PC survival.…”

High Rate of Antibody Secretion Is not Integral to Plasma Cell Differentiation as Revealed by XBP-1 Deficiency

“…Master regulators such as Blimp-1 or IFN regulatory factor 4 (IRF4) belong to this latter group and are responsible for repressing transcription of B cell genes or actively promoting the expression of ASC genes, respectively (4-9). X-box binding protein 1 (XBP-1) is a transcription factor also implicated in plasma cell differentiation, although its mechanism of action is less well defined (10)(11)(12)(13). XBP-1 has a role in the unfolded protein response (UPR) that is induced when the endoplasmic reticulum (ER) is overloaded with unfolded proteins (14,15).…”

“…It is thus not surprising that defective expression of XBP-1 impacts on the normal operation of a plasma cell. The role of XBP-1 in the development of plasma cells is, however, proposed to extend beyond its function in the UPR (10,20). Although XBP-1 is expressed at a low level throughout B cell development, expression is induced dramatically during plasma cell differentiation in response to cytokines such as IL-4 (11).…”