Regulation of Tcrb recombination ordering by c-Fos-dependent RAG deposition
Regulation of Tcrb recombination ordering by c-Fos-dependent RAG deposition
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通过 c-Fos 依赖性 RAG 沉积调节 Tcrb 重组顺序
DOI：
10.1038/ni.1614
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发表时间：
2008-07-01
影响因子：
30.5
通讯作者：
Liu, Xiaolong
中科院分区：
文献类型：
--
作者：
Wang, Xiaoming;Xiao, Gang;Liu, Xiaolong
抗原受体可变(多样性)连接(V(D)J)在编码T细胞抗原受体-β(Tcrb)的位点上的重组是有序的，D-β-to-J(Beta)组装先于V-beta-to-DJ(Beta)连接。这种“首选”重排顺序背后的分子机制尚不清楚。在这里，我们发现D-β23碱基对重组信号序列(D-β23-RSS)包含与AP-1结合的特定AP-1转录因子结合位点及其组分c-Fos在特定阶段表达。基于细胞的重组分析表明，c-Fos直接与RAG重组酶相互作用，并促进其沉积到DB 23-RSS，从而赋予DJ(β)重组的优先权。C-Fos的缺失降低了Tcrb的重组效率，扰乱了体内重组的有序性。我们的结果显示，c-Fos作为Tcrb重组的直接调节因子具有意想不到的功能，而不是通常的转录调节因子，并为重组排序的机制提供了新的见解。
Antigen receptor variable-(diversity)-joining (V(D)J)recombination at the locus encoding the T cell antigen receptor-beta (Tcrb)is ordered, with D-beta-to-J(beta) assembly preceding V-beta-to-DJ(beta) joining. The molecular mechanism underlying this 'preferred' order of rearrangement remains unclear. Here we show that the D-beta 23-base pair recombination signal sequence (D-beta 23-RSS)contains a specific AP-1 transcription factor-binding site bound by AP-1 and its component c-Fos expressed at a specific stage. Cell-based recombination assays suggested that c-Fos interacted directly with the RAG recombinase and enhanced its deposition to Db 23-RSSs, thus conferring the priority of DJ(beta) recombination. Loss of c-Fos decreased Tcrb recombination efficiency and disrupted recombination ordering in vivo. Our results show an unexpected function for c-Fos as a direct regulator of Tcrb recombination, rather than its usual function as a transcription regulator, and provide new insight into the mechanisms of recombination ordering.