The unfolded protein response sensor IRE1α is required at 2 distinct steps in B cell lymphopoiesis

B lymphocyte differentiation is coordinated with the induction of high-level Ig secretion and expansion of the secretory pathway. Upon accumulation of unfolded proteins in the lumen of the ER, cells activate an intracellular signaling pathway termed the unfolded protein response (UPR). Two major proximal sensors of the UPR are inositol-requiring enzyme 1 (IRE1), an ER transmembrane protein kinase/endoribonuclease, and ER-resident eukaryotic translation initiation factor 2 (eIF2) kinase (PERK). To elucidate whether the UPR plays an important role in lymphopoiesis, we carried out reconstitution of recombinase-activating gene 2-deficient (rag2 -/-) mice with hematopoietic cells defective in either IRE1-or PERK-mediated signaling. IRE1-deficient (ire1 -/-) HSCs can proliferate and give rise to pro-B cells that home to bone marrow. However, IRE1, but not its catalytic activities, is required for Ig gene rearrangement and production of B cell receptors (BCRs). Analysis of rag2 -/-mice transplanted with IRE1 trans-dominant-negative bone marrow cells demonstrated an additional requirement for IRE1 in B lymphopoiesis: both the IRE1 kinase and RNase catalytic activities are required to splice the mRNA encoding X-box-binding protein 1 (XBP1) for terminal differentiation of mature B cells into antibody-secreting plasma cells. Furthermore, UPR-mediated translational control through eIF2 phosphorylation is not required for B lymphocyte maturation and/or plasma cell differentiation. These results suggest specific requirements of the IRE1-mediated UPR subpathway in the early and late stages of B lymphopoiesis.