title: Transcription elongation factor ELL2 drives Ig secretory-specific mRNA production and the unfolded protein response.
abstract: Differentiation of B cells into Ab-secreting cells induces changes in gene transcription, IgH RNA processing, the unfolded protein response (UPR), and cell architecture. The transcription elongation factor eleven nineteen lysine-rich leukemia gene (ELL2) stimulates the processing of the secreted form of the IgH mRNA from the H chain gene. Mice (mus musculus) with the ELL2 gene floxed in either exon 1 or exon 3 were constructed and crossed to CD19-driven cre/CD19(+). The B cell-specific ELL2 conditional knockouts (cKOs; ell2(loxp/loxp) CD19(cre/+)) exhibit curtailed humoral responses both in 4-hydroxy-3-nitrophenyl acetyl-Ficoll and in 4-hydroxy-3-nitrophenyl acetyl-keyhole limpet hemocyanin immunized animals; recall responses were also diminished. The number of immature and recirculating B cells in the bone marrow is increased in the cKOs, whereas plasma cells in spleen are reduced relative to control animals. There are fewer IgG1 Ab-producing cells in the bone marrow of cKOs. LPS ex vivo-stimulated B220(lo)CD138(+) cells from ELL2-deficient mouse spleens are 4-fold less abundant than from control splenic B cells; have a paucity of secreted IgH; and have distended, abnormal-appearing endoplasmic reticulum. IRE1α is efficiently phosphorylated, but the amounts of Ig κ, ATF6, BiP, Cyclin B2, OcaB (BOB1, Pou2af1), and XBP1 mRNAs, unspliced and spliced, are severely reduced in ELL2-deficient cells. ELL2 enhances the expression of BCMA (also known as Tnfrsf17), which is important for long-term survival. Transcription yields from the cyclin B2 and the canonical UPR promoter elements are upregulated by ELL2 cDNA. Thus, ELL2 is important for many aspects of Ab secretion, XBP1 expression, and the UPR.
authors.affiliation: Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15261; and.
authors.forename: Kyung Soo
authors.initials: KS
authors.lastname: Park
authors.affiliation: Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15261; and.
authors.forename: Ian
authors.initials: I
authors.lastname: Bayles
authors.affiliation: Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15261; and.
authors.forename: Alec
authors.initials: A
authors.lastname: Szlachta-McGinn
authors.affiliation: Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15261; and.
authors.forename: Joshua
authors.initials: J
authors.lastname: Paul
authors.affiliation: Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15261; and.
authors.forename: Julie
authors.initials: J
authors.lastname: Boiko
authors.affiliation: Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15261; and.
authors.forename: Patricia
authors.initials: P
authors.lastname: Santos
authors.affiliation: Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15261; and.
authors.forename: June
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Urology, University of Pittsburgh Cancer Institute, Shadyside Medical Center, Pittsburgh, PA 15232.
authors.forename: Zhou
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15261; and.
authors.forename: Lisa
authors.initials: L
authors.lastname: Borghesi
authors.affiliation: Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15261; and milcarek@pitt.edu.
authors.forename: Christine
authors.initials: C
authors.lastname: Milcarek
mesh_terms: D000818:Animals; D018941:Antigens, CD19 / Q000235:genetics / Q000378:metabolism; D016175:B-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology / Q000378:metabolism / Q000648:ultrastructure; D002454:Cell Differentiation; D017353:Gene Deletion; D015870:Gene Expression; D023061:Gene Order; D018390:Gene Targeting; D056426:Genetic Loci; D007143:Immunoglobulin Heavy Chains / Q000235:genetics / Q000378:metabolism; D007136:Immunoglobulins / Q000235:genetics* / Q000378:metabolism; D016130:Immunophenotyping; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics*; D014158:Transcription, Genetic; D035602:Transcriptional Elongation Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D056811:Unfolded Protein Response
chemical_list: D018941:Antigens, CD19; C568074:ELL2 protein, mouse; D007143:Immunoglobulin Heavy Chains; D007136:Immunoglobulins; D012333:RNA, Messenger; D035602:Transcriptional Elongation Factors