CNOT3 contributes to early B cell development by controlling Igh rearrangement and p53 mRNA stability.
CNOT3 contributes to early B cell development by controlling Igh rearrangement and p53 mRNA stability.
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DOI：
10.1084/jem.20150384
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发表时间：
2015-08-24
期刊：
影响因子：
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通讯作者：
Kurosaki T
中科院分区：
文献类型：
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作者：
Inoue T;Morita M;Hijikata A;Fukuda-Yuzawa Y;Adachi S;Isono K;Ikawa T;Kawamoto H;Koseki H;Natsume T;Fukao T;Ohara O;Yamamoto T;Kurosaki T
井上等人。报道称 CNOT3 是 CCR4-NOT 去腺苷酸酶复合物的一个亚基，调节 mRNA 衰减和翻译抑制，控制 Igh 基因重排并破坏肿瘤抑制因子 p53 mRNA 的稳定性。 CNOT3 的缺失会导致原 B 细胞向前 B 细胞的转变受阻。 CCR4-NOT 去腺苷酸酶复合物在 mRNA 衰减和 Poly(A) 尾缩短诱导的翻译抑制中发挥着至关重要的作用。尽管该复合物各成分的体外活性已得到很好的表征，但其在免疫细胞中的体内作用仍不清楚。在这里，我们发现，缺乏该复合物 CNOT3 亚基的小鼠，特别是 B 细胞中，在原 B 细胞向前 B 细胞的转变中存在发育障碍。 CNOT3 调节免疫球蛋白重链 (Igh) 基因座 VH 区种系转录物的生成、基因座的压缩以及随后的 Igh 基因重排和肿瘤抑制因子 p53 mRNA 的不稳定。 CNOT3缺失时的发育缺陷可以通过p53的消融或引入预先重排的Igh转基因来部分挽救。因此，我们的数据表明，CCR4-NOT 复合物通过控制 Igh 重排和破坏 p53 mRNA 的稳定性来调节 B 细胞分化。
Inoue et al. report that CNOT3, a subunit of the CCR4–NOT deadenylase complex regulating mRNA decay and translational repression, controls Igh gene rearrangement and destabilizes the mRNA of the tumor suppressor p53. Loss of CNOT3 results in a block of pro- to pre–B cell transition. The CCR4–NOT deadenylase complex plays crucial roles in mRNA decay and translational repression induced by poly(A) tail shortening. Although the in vitro activities of each component of this complex have been well characterized, its in vivo role in immune cells remains unclear. Here we show that mice lacking the CNOT3 subunit of this complex, specifically in B cells, have a developmental block at the pro- to pre–B cell transition. CNOT3 regulated generation of germline transcripts in the VH region of the immunoglobulin heavy chain (Igh) locus, compaction of the locus, and subsequent Igh gene rearrangement and destabilized tumor suppressor p53 mRNA. The developmental defect in the absence of CNOT3 could be partially rescued by ablation of p53 or introduction of a pre-rearranged Igh transgene. Thus, our data suggest that the CCR4–NOT complex regulates B cell differentiation by controlling Igh rearrangement and destabilizing p53 mRNA.