title: Heterogeneous nuclear ribonucleoprotein L-like (hnRNPLL) and elongation factor, RNA polymerase II, 2 (ELL2) are regulators of mRNA processing in plasma cells.
abstract: B cells and plasma cells possess distinct RNA processing environments that respectively promote the expression of membrane-associated Ig by B cells versus the secretion of Ig by plasma cells. Through a combination of transcriptional profiling and screening using a lentiviral short-hairpin RNA interference library, we show that both the splicing factor hnRNPLL and the transcription elongation factor ELL2 modulate the ratio of secreted versus membrane-encoding Ighg2b transcripts in MPC11 plasmacytoma cell lines. hnRNPLL and ELL2 are both highly expressed in primary plasma cells relative to B cells, but hnRNPLL binds Ighg2b mRNA transcripts and promotes an increase in levels of the membrane-encoding Ighg2b isoform at the expense of the secreted Ighg2b isoform, whereas ELL2 counteracts this effect and drives Ig secretion by increasing the frequency of the secreted Ighg2b isoform. As in T cells, hnRNPLL also alters the splicing pattern of mRNA encoding the adhesion receptor CD44, promoting exon inclusion, and decreasing the overall level of CD44 expression. Further characterization of ELL2-dependent transcription by RNA-Seq revealed that ∼12% of transcripts expressed by plasma cells were differentially processed because of the activities of ELL2, including B-cell maturation antigen BCMA, a receptor with a defined role in plasma cell survival. Taken together, our data identify hnRNPLL and ELL2 as regulators of pre-mRNA processing in plasma cells.
authors.affiliation: Department of Pathology, Harvard Medical School and Immune Disease Institute and Program in Cellular and Molecular Medicine, Children's Hospital Boston, Boston, MA 02115, USA.
authors.forename: Micah J
authors.initials: MJ
authors.lastname: Benson
authors.forename: Tarmo
authors.initials: T
authors.lastname: Aijö
authors.forename: Xing
authors.initials: X
authors.lastname: Chang
authors.forename: John
authors.initials: J
authors.lastname: Gagnon
authors.forename: Utz J
authors.initials: UJ
authors.lastname: Pape
authors.forename: Vivek
authors.initials: V
authors.lastname: Anantharaman
authors.forename: L
authors.initials: L
authors.lastname: Aravind
authors.forename: Juha-Pekka
authors.initials: JP
authors.lastname: Pursiheimo
authors.forename: Shalini
authors.initials: S
authors.lastname: Oberdoerffer
authors.forename: X Shirley
authors.initials: XS
authors.lastname: Liu
authors.forename: Riitta
authors.initials: R
authors.lastname: Lahesmaa
authors.forename: Harri
authors.initials: H
authors.lastname: Lähdesmäki
authors.forename: Anjana
authors.initials: A
authors.lastname: Rao
mesh_terms: D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D005434:Flow Cytometry; D034441:Heterogeneous-Nuclear Ribonucleoproteins / Q000378:metabolism*; D018960:Hyaluronan Receptors / Q000378:metabolism; D007143:Immunoglobulin Heavy Chains / Q000235:genetics / Q000378:metabolism*; D047468:Immunoprecipitation; D051379:Mice; D008807:Mice, Inbred BALB C; D046228:Microarray Analysis; D010950:Plasma Cells / Q000378:metabolism / Q000502:physiology*; D020033:Protein Isoforms / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism / Q000502:physiology*; D060888:Real-Time Polymerase Chain Reaction; D017423:Sequence Analysis, RNA; D035602:Transcriptional Elongation Factors / Q000378:metabolism*
chemical_list: C568074:ELL2 protein, mouse; D034441:Heterogeneous-Nuclear Ribonucleoproteins; D018960:Hyaluronan Receptors; D007143:Immunoglobulin Heavy Chains; D020033:Protein Isoforms; D012333:RNA, Messenger; D035602:Transcriptional Elongation Factors; C534662:hnRNPLL protein, mouse