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Review
. 2005 Feb;115(2):224-7.
doi: 10.1172/JCI24238.

Birth pangs: the stressful origins of lymphocytes

Shiv Pillai  1
Affiliations
Review

Birth pangs: the stressful origins of lymphocytes

Shiv Pillai. J Clin Invest. 2005 Feb.

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.

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Figures

Figure 1
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
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 DH to JH and VH to DJH 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.
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References

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