Birth pangs: the stressful origins of lymphocytes

Abstract

Inositol-requiring enzyme 1 (IRE1) is a transmembrane protein that signals from the ER and contributes to the generation of an active spliced form of the transcriptional regulator X-box-binding protein 1 (XBP1). XBP1 is required for the terminal differentiation of B lymphocytes into plasma cells, and IRE1 also participates in this differentiation event. A study in this issue of the JCI reveals, quite unexpectedly, that IRE1 is also required early in B lymphocyte development for the induction of the machinery that mediates Ig gene rearrangement.

Figure 1

Multiple sensors initiate the UPR in vertebrates. IRE1α and PERK are integral-membrane ER kinases whose lumenal domains are triggered by misfolded proteins in the ER. IRE1α and its yeast homolog, IRE1, contain a lumenal stress-sensing domain (blue) as well as cytosolic kinase (magenta) and endoribonuclease (RNaseL, red) domains. ATF6 is another stress sensor, which is cleaved in response to stress to yield a fragment (green) that is transported to the nucleus. Both ATF6 and Blimp-1 (not shown) may contribute to the transcriptional induction of XBP1. Very little is understood as to how IRE1α, a kinase that is activated by unfolded proteins in the ER, contributes to the induction of Rag1, Rag2, and TdT to initiate and sustain V(D)J recombination during early B cell development.

Figure 2

A simplified overview of B cell development. Differentiation is initiated in the bone marrow in an antigen-independent manner and is completed in the periphery in response to antigenic challenge. Rearrangement of the Ig heavy chain is initiated in pro–B cells and involves sequential D_H to J_H and V_H to DJ_H rearrangements. Once light chain rearrangement is completed, B cells emigrate to the periphery and give rise to multiple peripheral lineages (not shown). Peripheral B cells activated by either T cell–dependent or T cell–independent antigens differentiate into plasma cells. In this issue, Zhang et al. (15) demonstrate that IRE1 is required for V(D)J recombination early in B cell development, but in a kinase- and endoribonuclease-independent fashion. IRE1 kinase and endoribonuclease activities are required for the splicing of XBP1 and plasma cell development. Pre-BCR, pre–B cell receptor.