Zhang Zhixin, Espinoza Celia R, Yu Zhihong, Stephan Robert, He Ti, Williams G Stuart, Burrows Peter D, Hagman James, Feeney Ann J, Cooper Max D
Division of Developmental and Clinical Immunology, University of Alabama at Birmingham, 35294, USA.
Nat Immunol. 2006 Jun;7(6):616-24. doi: 10.1038/ni1339. Epub 2006 May 7.
Immunoglobulin rearrangement from variable heavy chain (V(H)) to diversity (D)-joining heavy chain (J(H)), which occurs exclusively in B lineage cells, is impaired in mice deficient for the B lineage-specific transcription factor Pax5. Conversely, ectopic Pax5 expression in thymocytes promotes the rearrangement of D(H)-proximal V(H)7183 genes. In exploring the mechanism for Pax5 regulation of V(H)-to-DJ(H) recombination, we have identified multiple Pax5 binding sites in the coding regions of human and mouse V(H) gene segments. Pax5 bound to those sites in vitro and occupied V(H) genes in early human and mouse B lineage cells. Moreover, Pax5 interacted with the recombination-activating gene 1 (RAG1)-RAG2 complex to enhance RAG-mediated V(H) recombination signal sequence cleavage and recombination of a V(H) gene substrate. These findings indicate a direct activating function for Pax5 in RAG-mediated immunoglobulin V(H)-to-DJ(H) recombination.
免疫球蛋白从可变重链（V(H)）到多样性（D）-连接重链（J(H)）的重排仅发生在B淋巴细胞系细胞中，在缺乏B淋巴细胞系特异性转录因子Pax5的小鼠中这种重排受损。相反，胸腺细胞中异位表达的Pax5可促进D(H)近端V(H)7183基因的重排。在探索Pax5调控V(H)到DJ(H)重组的机制时，我们在人和小鼠V(H)基因片段的编码区鉴定出多个Pax5结合位点。Pax5在体外与这些位点结合，并在早期人和小鼠B淋巴细胞系细胞中占据V(H)基因。此外，Pax5与重组激活基因1（RAG1）-RAG2复合物相互作用，以增强RAG介导的V(H)重组信号序列切割及V(H)基因底物的重组。这些发现表明Pax5在RAG介导的免疫球蛋白V(H)到DJ(H)重组中具有直接激活功能。
