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- Title
RNA exosome drives early B cell development via noncoding RNA processing mechanisms.
- Authors
Laffleur, Brice; Batista, Carolina R.; Zhang, Wanwei; Lim, Junghyun; Yang, Biao; Rossille, Delphine; Wu, Lijing; Estrella, Jerson; Rothschild, Gerson; Pefanis, Evangelos; Basu, Uttiya
- Abstract
B cell development is linked to successful V(D)J recombination, allowing B cell receptor expression and ultimately antibody secretion for adaptive immunity. Germline noncoding RNAs (ncRNAs) are produced at immunoglobulin (Ig) loci during V(D)J recombination, but their function and posttranscriptional regulation are incompletely understood. Patients with trichohepatoenteric syndrome, characterized by RNA exosome pathway component mutations, exhibit lymphopenia, thus demonstrating the importance of ncRNA surveillance in B cell development in humans. To understand the role of RNA exosome in early B cell development in greater detail, we generated mouse models harboring a B cell–specific cre allele (Mb1cre), coupled to conditional inversion-deletion alleles of one RNA exosome core component (Exosc3) or RNase catalytic subunits (Exosc10 or Dis3). We noticed increased expression of RNA exosome subunits during V(D)J recombination, whereas a B cell developmental blockade at the pro–B cell stage was observed in the different knockout mice, overlapping with a lack of productive rearrangements of VDJ genes at the Ig heavy chain (Igh). This unsuccessful recombination prevented differentiation into pre–B cells, with accumulation of ncRNAs and up-regulation of the p53 pathway. Introduction of a prearranged Igh VDJ allele partly rescued the pre–B cell population in Dis3-deficient cells, although V-J recombination defects were observed at Ig light chain kappa (Igκ), preventing subsequent B cell development. These observations demonstrated that the RNA exosome complex is important for Igh and Igκ recombination and establish the relevance of RNA processing for optimal diversification at these loci during B cell development. B cells do not Dis3 RNA exosomes: RNA exosomes are complexes that degrade RNA and are involved in cell development. How RNA exosomes affect B cell development is unclear. Here, Laffleur et al. found that the expression of various RNA exosome machinery components (Exosc10, Dis3, and Exosc3) were increased at the pro– and pre–B cell phase of B cell development. They made B cell conditional knockout mice for these RNA exosome components and found that these knockouts each led to arrested B cell development at the pro–B cell stage, which correlated to p53-induced cell death and lack of V(D)J recombination. Reintroducing recombination into the Dis3 knockout mice partially rescued this arrest. Thus, the RNA exosome is crucial for B cell development.
- Publication
Science Immunology, 2022, Vol 7, Issue 72, p1
- ISSN
2470-9468
- Publication type
Article
- DOI
10.1126/sciimmunol.abn2738