E3-ubiquitin ligase Nedd4 determines the fate of AID-associated RNA polymerase II in B cells.
E3-ubiquitin ligase Nedd4 determines the fate of AID-associated RNA polymerase II in B cells.
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DOI：
10.1101/gad.210211.112
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发表时间：
2013-08-15
影响因子：
10.5
通讯作者：
Basu U
中科院分区：
文献类型：
--
作者：
Sun J;Keim CD;Wang J;Kazadi D;Oliver PM;Rabadan R;Basu U
在b淋巴细胞类开关重组过程中，免疫球蛋白（Ig）位点的突变需要RNA polii依赖性靶向DNA突变子AID，但其机制尚不清楚。Sun等人现在发现e3 -泛素连接酶Nedd4在Ig开关区域破坏了艾滋病相关RNA polII的稳定性。Nedd4活性的丧失导致RNA外泌体底物在AID靶基因上积累。本研究将RNA polII暂停后的非编码RNA加工与类开关重组过程中的AID调控联系起来。在类开关重组（CSR）和体细胞超突变过程中，B淋巴细胞免疫球蛋白位点的程序性突变需要RNA聚合酶II （polII）转录复合物依赖的DNA突变激活诱导胞苷脱氨酶（AID）靶向。AID通过转录依赖机制将免疫球蛋白（Ig）底物序列上的胞苷残基脱胺，这种活性是由RNA polII停滞辅助因子Spt5和11亚基细胞非编码RNA 3 ‘ -5 ’外核水解加工复合物RNA外泌体刺激的。RNA外泌体识别免疫球蛋白位点RNA底物以刺激其体内底物序列上的AID DNA脱氨活性的机制是一个重要的问题。在这里，我们报道e3 -泛素连接酶Nedd4通过泛素化事件破坏艾滋病相关RNA polII的稳定性，导致在Ig位点和其他全基因组aids靶序列上产生3 '端游离RNA外泌体RNA底物。我们发现，B细胞缺乏Nedd4活性会导致AID靶基因上RNA外泌体底物的积累和CSR缺陷。综上所述，我们的研究将RNA polII暂停后的非编码RNA加工与突变子AID蛋白的调节联系起来。我们的研究还发现Nedd4是由停滞RNA polII全基因组产生的非编码RNA的调节因子。
During B-lymphocyte class switch recombination, mutagenesis of the immunoglobulin (Ig) locus requires RNA polII-dependent targeting of the DNA mutator AID, yet the mechanism is unknown. Sun et al. now show that E3-ubiquitin ligase Nedd4 destabilizes AID-associated RNA polII at Ig switch regions. Loss of Nedd4 activity leads to RNA exosome substrate accumulation at AID target genes. This study links noncoding RNA processing following RNA polII pausing with AID regulation during class switch recombination. Programmed mutagenesis of the immunoglobulin locus of B lymphocytes during class switch recombination (CSR) and somatic hypermutation requires RNA polymerase II (polII) transcription complex-dependent targeting of the DNA mutator activation-induced cytidine deaminase (AID). AID deaminates cytidine residues on substrate sequences in the immunoglobulin (Ig) locus via a transcription-dependent mechanism, and this activity is stimulated by the RNA polII stalling cofactor Spt5 and the 11-subunit cellular noncoding RNA 3′–5′ exonucleolytic processing complex RNA exosome. The mechanism by which the RNA exosome recognizes immunoglobulin locus RNA substrates to stimulate AID DNA deamination activity on its in vivo substrate sequences is an important question. Here we report that E3-ubiquitin ligase Nedd4 destabilizes AID-associated RNA polII by a ubiquitination event, leading to generation of 3′ end free RNA exosome RNA substrates at the Ig locus and other AID target sequences genome-wide. We found that lack of Nedd4 activity in B cells leads to accumulation of RNA exosome substrates at AID target genes and defective CSR. Taken together, our study links noncoding RNA processing following RNA polII pausing with regulation of the mutator AID protein. Our study also identifies Nedd4 as a regulator of noncoding RNAs that are generated by stalled RNA polII genome-wide.
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