title: The unfolded protein response sensor IRE1alpha is required at 2 distinct steps in B cell lymphopoiesis.
abstract: 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 1alpha (IRE1alpha), an ER transmembrane protein kinase/endoribonuclease, and ER-resident eukaryotic translation initiation factor 2alpha (eIF2alpha) 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 IRE1alpha- or PERK-mediated signaling. IRE1alpha-deficient (ire1alpha-/-) HSCs can proliferate and give rise to pro-B cells that home to bone marrow. However, IRE1alpha, but not its catalytic activities, is required for Ig gene rearrangement and production of B cell receptors (BCRs). Analysis of rag2-/- mice transplanted with IRE1alpha trans-dominant-negative bone marrow cells demonstrated an additional requirement for IRE1alpha in B lymphopoiesis: both the IRE1alpha 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 eIF2alpha phosphorylation is not required for B lymphocyte maturation and/or plasma cell differentiation. These results suggest specific requirements of the IRE1alpha-mediated UPR subpathway in the early and late stages of B lymphopoiesis.
authors.affiliation: Department of Biological Chemistry and Howard Hughes Medical Institute, University of Michigan Medical Center, Ann Arbor, Michigan 48109, USA.
authors.forename: Kezhong
authors.initials: K
authors.lastname: Zhang
authors.forename: Hetty N
authors.initials: HN
authors.lastname: Wong
authors.forename: Benbo
authors.initials: B
authors.lastname: Song
authors.forename: Corey N
authors.initials: CN
authors.lastname: Miller
authors.forename: Donalyn
authors.initials: D
authors.lastname: Scheuner
authors.forename: Randal J
authors.initials: RJ
authors.lastname: Kaufman
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000502:physiology; D016026:Bone Marrow Transplantation; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism; D004722:Endoribonucleases / Q000378:metabolism; D015322:Gene Rearrangement, B-Lymphocyte / Q000235:genetics / Q000502:physiology; D007136:Immunoglobulins / Q000235:genetics / Q000378:metabolism; D038041:Lymphopoiesis / Q000235:genetics / Q000502:physiology*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000378:metabolism; D010950:Plasma Cells / Q000502:physiology*; D011489:Protein Denaturation / Q000502:physiology; D017510:Protein Folding; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D012326:RNA Splicing / Q000235:genetics / Q000502:physiology; D011947:Receptors, Antigen, B-Cell / Q000235:genetics / Q000378:metabolism; D000071701:Regulatory Factor X Transcription Factors; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; D019892:eIF-2 Kinase / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D007136:Immunoglobulins; D008565:Membrane Proteins; D009687:Nuclear Proteins; C499308:Rag2 protein, mouse; D011947:Receptors, Antigen, B-Cell; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; C064655:V(D)J recombination activating protein 2; D000071717:X-Box Binding Protein 1; C000605544:Xbp1 protein, mouse; C486556:Ern2 protein, mouse; D017346:Protein Serine-Threonine Kinases; D019892:eIF-2 Kinase; D004722:Endoribonucleases; C051012:splicing endonuclease