Aire employs a histone-binding module to mediate immunological tolerance, linking chromatin regulation with organ-specific autoimmunity
Aire employs a histone-binding module to mediate immunological tolerance, linking chromatin regulation with organ-specific autoimmunity
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DOI：
10.1073/pnas.0808470105
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发表时间：
2008-10-14
影响因子：
11.1
通讯作者：
Mathis, Diane
中科院分区：
文献类型：
--
作者：
Koh, Andrew S.;Kuo, Alex J.;Mathis, Diane
Aire诱导胸腺髓上皮细胞外周组织抗原WAS的异位表达，促进免疫耐受。从组蛋白肽的广泛筛选开始，我们证明了这种单一因子控制数千个基因转录的机制涉及识别组蛋白H3的氨基末端尾部，而不是通过Aire的植物同源结构域（PHD）手指之一识别其他组蛋白。某些H3尾部的翻译后修饰，特别是H3K4上的二甲基化或三甲基化，会破坏Aire的结合，而其他修饰则是耐受的。最近报道了braf -组蛋白去乙酰化酶复合物80和DNA甲基转移酶3L类似的PHD指- h3尾部结合特性；序列比对、分子模型和生化分析表明，这些因子与Aire具有共同的结构-功能关系。此外，自身免疫性多内分泌病-念珠菌病-外胚层营养不良症的某些PHD1突变损害了Aire对H3的识别。体外结合试验表明，Aire与核小体之间存在直接的物理相互作用，这在一定程度上是由其对DNA的亲和力所支持的。在体内，Aire与缺失H3K4me3的染色体区域的相互作用依赖于其H3尾部结合活性，这种结合对于PTAs编码基因的上调是必要的，但不是充分的。因此，Aire作为组蛋白结合模块的活性介导PTAs的胸腺显示，从而促进自身耐受性并防止器官特异性自身免疫。
Aire induces ectopic expression of peripheral tissue antigens WAS) in thymic medullary epithelial cells, which promotes immunological tolerance. Beginning with a broad screen of histone peptides, we demonstrate that the mechanism by which this single factor controls the transcription of thousands of genes involves recognition of the amino-terminal tail of histone H3, but not of other histones, by one of Aire's plant homeodomain (PHD) fingers. Certain posttranslational modifications of H3 tails, notably dimethylation or trimethylation at H3K4, abrogated binding by Aire, whereas others were tolerated. Similar PHD finger-H3 tail-binding properties were recently reported for BRAF-histone deacetylase complex 80 and DNA methyltransferase 3L; sequence alignment, molecular modeling, and biochemical analyses showed these factors and Aire to have structure-function relationships in common. In addition, certain PHD1 mutations underlying the polyendocrine disorder autoimmune polyendocrinopathy-candidiases-ectodermaldystrophy compromised Aire recognition of H3. In vitro binding assays demonstrated direct physical interaction between Aire and nucleosomes, which was in part buttressed by its affinity to DNA. In vivo Aire interactions with chromosomal regions depleted of H3K4me3 were dependent on its H3 tail-binding activity, and this binding was necessary but not sufficient for the up-regulation of genes encoding PTAs. Thus, Aire's activity as a histone-binding module mediates the thymic display of PTAs that promotes self-tolerance and prevents organ-specific autoimmunity.