Verkoczy Laurent, Aït-Azzouzene Djemel, Skog Patrick, Märtensson Annica, Lang Julie, Duong Bao, Nemazee David
Department of Immunology, The Scripps Research Institute, La Jolla, California 92037, USA.
Immunity. 2005 Apr;22(4):519-31. doi: 10.1016/j.immuni.2005.03.006.
In developing B cells, expression of surface immunoglobulin is an important signal to terminate recombinase activator gene (RAG) expression and V(D)J recombination. However, autoreactive antigen receptors instead promote continued gene rearrangement and receptor editing. The regulation by B cell receptor (BCR) signaling of RAG expression and editing is poorly understood. We report that in editing-competent cells BCR ligand-induced RAG mRNA expression is regulated at the level of RAG transcription, rather than mRNA stability. In immature B cells carrying innocuous receptors, RAG expression appears to be under rapidly reversible negative regulation. Studies involving transduction of a superrepressive (sr) I kappa B alpha protein indicate that NF-kappaB/Rel proteins promote RAG transcription. Interestingly, NF kappa B1-deficient cells overexpress RAG and undergo an exaggerated receptor editing response. Our data implicate NF kappa B transcription factors in the BCR-mediated regulation of RAG locus transcription. Rapidly activated NF kappa B pathways may facilitate prompt antigen receptor-regulated changes in RAG expression important for editing and haplotype exclusion.
在B细胞发育过程中，表面免疫球蛋白的表达是终止重组酶激活基因（RAG）表达和V(D)J重组的重要信号。然而，自身反应性抗原受体会促进基因的持续重排和受体编辑。目前对B细胞受体（BCR）信号传导对RAG表达和编辑的调控了解甚少。我们报告，在具有编辑能力的细胞中，BCR配体诱导的RAG mRNA表达是在RAG转录水平而非mRNA稳定性水平受到调控。在携带无害受体的未成熟B细胞中，RAG表达似乎受到快速可逆的负调控。涉及转导超抑制性（sr）IκBα蛋白的研究表明，NF-κB/Rel蛋白促进RAG转录。有趣的是，NFκB1缺陷细胞会过度表达RAG并经历过度的受体编辑反应。我们的数据表明NFκB转录因子参与了BCR介导的RAG基因座转录调控。快速激活的NFκB信号通路可能有助于抗原受体对RAG表达进行快速调控，这对编辑和单倍型排除很重要。
