title: miR-148a promotes plasma cell differentiation and targets the germinal center transcription factors Mitf and Bach2.
abstract: B cells undergo affinity maturation and class switch recombination of their immunoglobulin receptors during a germinal center (GC) reaction, before they differentiate into long-lived antibody-secreting plasma cells (PCs). Transcription factors such as Bach2 and Mitf are essential during this process, as they delay premature differentiation of GC B cells by repressing Blimp-1 and IRF4, two transcription factors required for terminal PC differentiation. Therefore, Bach2 and Mitf expression must be attenuated in activated B cells to allow terminal PC differentiation, but the precise mechanism remains enigmatic. Here, we provide evidence that miR-148a, a small noncoding microRNA, fosters PC differentiation and survival. Next-generation sequencing revealed that miR-148a is the most abundant microRNA in primary human and murine PCs, and its expression is upregulated in activated murine B cells and coincides with Blimp-1 synthesis. miR-148a targets Bach2, Mitf and proapoptotic factors such as PTEN and Bim. When prematurely expressed, miR-148a promotes the differentiation and survival of plasmablasts and reduces frequencies of IgG1(+) cells in primary B-cell cultures. In summary, we propose that miR-148a is a new player in the regulatory network controlling terminal PC differentiation and could, therefore, be a therapeutic target for interfering with PC differentiation and survival.
authors: Division of Molecular Immunology, Department of Internal Medicine III, Nikolaus-Fiebiger-Center for Molecular Medicine, University of Erlangen-Nürnberg, Erlangen, Germany.
authors: Martina
authors: M
authors: Porstner
authors: Rebecca
authors: R
authors: Winkelmann
authors: Patrick
authors: P
authors: Daum
authors: Julia
authors: J
authors: Schmid
authors: Katharina
authors: K
authors: Pracht
authors: Joana
authors: J
authors: Côrte-Real
authors: Sandra
authors: S
authors: Schreiber
authors: Claudia
authors: C
authors: Haftmann
authors: Andreas
authors: A
authors: Brandl
authors: Mir-Farzin
authors: MF
authors: Mashreghi
authors: Kolja
authors: K
authors: Gelse
authors: Manuela
authors: M
authors: Hauke
authors: Ina
authors: I
authors: Wirries
authors: Markus
authors: M
authors: Zwick
authors: Edith
authors: E
authors: Roth
authors: Andreas
authors: A
authors: Radbruch
authors: Jürgen
authors: J
authors: Wittmann
authors: Hans-Martin
authors: HM
authors: Jäck
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis; D001402:B-Lymphocytes / Q000276:immunology; D001483:Base Sequence; D050976:Basic-Leucine Zipper Transcription Factors / Q000096:biosynthesis*; D000072224:Bcl-2-Like Protein 11; D002454:Cell Differentiation / Q000235:genetics* / Q000276:immunology; D002470:Cell Survival; D055785:Gene Knockdown Techniques; D018858:Germinal Center / Q000166:cytology; D057809:HEK293 Cells; D006801:Humans; D017578:Immunoglobulin Class Switching / Q000235:genetics / Q000276:immunology; D050835:Interferon Regulatory Factors / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000235:genetics; D008565:Membrane Proteins / Q000096:biosynthesis; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000502:physiology*; D051739:Microphthalmia-Associated Transcription Factor / Q000096:biosynthesis*; D051059:PTEN Phosphohydrolase / Q000096:biosynthesis; D010950:Plasma Cells / Q000166:cytology*; D000074462:Positive Regulatory Domain I-Binding Factor 1; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis; D012097:Repressor Proteins / Q000096:biosynthesis; D017422:Sequence Analysis, DNA; D000099218:Interferon Regulatory Factor-4
chemical_list: D051017:Apoptosis Regulatory Proteins; D050976:Basic-Leucine Zipper Transcription Factors; D000072224:Bcl-2-Like Protein 11; D050835:Interferon Regulatory Factors; D008565:Membrane Proteins; D035683:MicroRNAs; D051739:Microphthalmia-Associated Transcription Factor; D051059:PTEN Phosphohydrolase; D000074462:Positive Regulatory Domain I-Binding Factor 1; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D000099218:Interferon Regulatory Factor-4; C491123:BACH2 protein, human; C000606775:BCL2L11 protein, human; C000606776:Bcl2l11 protein, mouse; C550570:MIRN148 microRNA, human; C497234:MITF protein, human; C087042:PRDM1 protein, human; C494929:PTEN protein, human
keywords: Bach2, Mitf; Blimp-1; B cells; MicroRNAs; Plasma cell differentiation; miR-148a