Electron micrograph of a mature plasma cell showing extensive endoplasmic reticulum. Reproduced from Bosman et al. (1969. J. Exp. Med. 129:1029–1044).

The development of antibody-secreting plasma cells is crippled in the absence of the transcription factor XBP-1 (X-box binding protein). Based on the role of XBP-1 in the endoplasmic reticulum (ER) unfolded protein response (UPR), it was speculated that the ER needs this protein to cope with the ramped-up protein production that accompanies plasma cell differentiation. On page 505, Tirosh and coworkers show instead that XBP-1 controls immunoglobulin synthesis posttranslationally, independently of its role in orchestrating the UPR.

The UPR is a signaling system that ensures proper folding, processing, and degradation of proteins in the ER. When protein production exceeds the ER's quality control capacity, XBP-1 drives the expression of additional proteins, such as chaperones and degradative enzymes that help to absorb the extra workload.

The prevailing explanation for the XBP-1 requirement in plasma cell development—that the ER otherwise becomes lethally clogged with excess immunoglobulin protein—is called into question by the new data from Ploegh's group. The study shows that protein degradation in the ER was intact in the absence of XBP-1, suggesting that the ER quality control pathway in B cells does not require XBP-1. Instead, XBP-1 was required for the sustained synthesis of IgM in primary B cells. This defect was specific for IgM heavy chain protein, as synthesis and trafficking of other proteins were unaffected.

Despite the drop in IgM protein production, IgM heavy chain transcripts were not decreased in XBP-1–deficient cells, suggesting that XBP-1 affected translation. Although the mechanism is not yet clear, Ploegh suspects that XBP-1 might drive the expression of microRNAs that regulate translation, similar to those that control gene expression during neuronal development in worms and cell fate decisions in developing hematopoietic cells.