Intronic regulation of Aire expression by Jmjd6 for self-tolerance induction in the thymus.
Intronic regulation of Aire expression by Jmjd6 for self-tolerance induction in the thymus.
复制标题
DOI：
10.1038/ncomms9820
复制
发表时间：
2015-11-04
影响因子：
16.6
通讯作者：
Yoshinori F
中科院分区：
文献类型：
--
作者：
Yanagihara T;Sanematsu F;Sato T;Uruno T;Duan X;Tomino T;Harada Y;Watanabe M;Wang Y;Tanaka Y;Nakanishi Y;Suyama M;Yoshinori F
胸腺有空间上不同的微环境，皮质和髓质，发育中的T细胞被选择通过与胸腺基质细胞的相互作用而成熟或死亡。胸腺髓质上皮细胞(MTECs)表达多种组织特异性自身抗原(TSAs)，以建立胸腺的免疫自我。TSAs的这种异位表达在很大程度上依赖于转录调控因子Aire，但控制Aire表达的机制仍不清楚。在这里，我们证明了Jmjd6，一种催化剪接调节蛋白赖氨酸羟化的双加氧酶，对Aire的表达至关重要。虽然Jmjd6缺乏并不影响Aire转录本的丰度，但在缺乏Jmjd6的情况下，Aire基因的内含子2不能有效地剪接，导致mTECs中成熟的Aire蛋白显著减少，并在小鼠体内自发形成多器官自身免疫。这些结果突显了内含子调控在控制Aire蛋白表达中的重要性。Jmjd6是一种催化剪接调节蛋白赖氨酸羟化的双加氧酶。在这里，作者发现Jmjd6指导了髓质胸腺上皮细胞中中枢耐受调节因子Aire的剪接，并且Jmjd6缺乏导致Aire的丧失和小鼠的多器官自身免疫。
The thymus has spatially distinct microenvironments, the cortex and the medulla, where the developing T-cells are selected to mature or die through the interaction with thymic stromal cells. To establish the immunological self in the thymus, medullary thymic epithelial cells (mTECs) express diverse sets of tissue-specific self-antigens (TSAs). This ectopic expression of TSAs largely depends on the transcriptional regulator Aire, yet the mechanism controlling Aire expression itself remains unknown. Here, we show that Jmjd6, a dioxygenase that catalyses lysyl hydroxylation of splicing regulatory proteins, is critical for Aire expression. Although Jmjd6 deficiency does not affect abundance of Aire transcript, the intron 2 of Aire gene is not effectively spliced out in the absence of Jmjd6, resulting in marked reduction of mature Aire protein in mTECs and spontaneous development of multi-organ autoimmunity in mice. These results highlight the importance of intronic regulation in controlling Aire protein expression. Jmjd6 is a dioxygenase that catalyses lysyl hydroxylation of splicing regulatory proteins. Here the authors show that Jmjd6 directs splicing of a central tolerance regulator Aire in medullary thymic epithelial cells, and that Jmjd6 deficiency leads to loss of Aire and multi-organ autoimmunity in mice.