Heterogeneous nuclear ribonucleoprotein L-like (hnRNPLL) and elongation factor, RNA polymerase II, 2 (ELL2) are regulators of mRNA processing in plasma cells

被引:30
作者
Benson, Micah J. [1 ,2 ,3 ]
Aijo, Tarmo [4 ]
Chang, Xing [5 ]
Gagnon, John [1 ,2 ,3 ]
Pape, Utz J. [1 ,2 ,3 ,6 ,7 ]
Anantharaman, Vivek [8 ]
Aravind, L. [8 ]
Pursiheimo, Juha-Pekka [9 ,10 ]
Oberdoerffer, Shalini [11 ]
Liu, X. Shirley [6 ,7 ]
Lahesmaa, Riitta [9 ,10 ]
Lahdesmaki, Harri [4 ,9 ,10 ]
Rao, Anjana [1 ,2 ,3 ,5 ,12 ,13 ]
机构
[1] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA
[2] Childrens Hosp, Immune Dis Inst, Boston, MA 02115 USA
[3] Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA
[4] Aalto Univ, Sch Sci, Dept Informat & Comp Sci, FI-00076 Aalto, Finland
[5] La Jolla Inst Allergy & Immunol, Div Signaling & Gene Express, La Jolla, CA 92037 USA
[6] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02215 USA
[7] Harvard Univ, Sch Publ Hlth, Boston, MA 02215 USA
[8] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA
[9] Univ Turku, Turku Ctr Biotechnol, FI-20520 Turku, Finland
[10] Abo Akad Univ, FI-20520 Turku, Finland
[11] NCI, Ctr Canc Res, Mouse Canc Genet Program, Frederick, MD 21702 USA
[12] Univ Calif San Diego, Dept Pharmacol, La Jolla, CA 92037 USA
[13] Sanford Consortium Regenerat Med, La Jolla, CA 92037 USA
基金
美国国家卫生研究院; 芬兰科学院;
关键词
immunoglobulin; mRNA splicing; transcriptional elongation; B cell maturation antigen; B-CELL; IMMUNOGLOBULIN; POLYADENYLATION; MEMBRANE; EXPRESSION; SEQUENCE; CHAIN; GENE; SECRETION; CLEAVAGE;
D O I
10.1073/pnas.1214414109
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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 similar to 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.
引用
收藏
页码:16252 / 16257
页数:6
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