AIRE's CARD revealed, a new structure for central tolerance provokes transcriptional plasticity
AIRE's CARD revealed, a new structure for central tolerance provokes transcriptional plasticity
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DOI：
10.1074/jbc.m707211200
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发表时间：
2008-01-18
影响因子：
4.8
通讯作者：
Rich, Tina
中科院分区：
文献类型：
--
作者：
Ferguson, Brian J.;Alexander, Clare;Rich, Tina
发育中的T细胞在胸腺中遇到外周自身抗原，以删除自身反应克隆。目前已知，胸腺髓质上皮细胞表达的自身免疫调节蛋白(AIRE)在调节胸腺这些外周组织特异性抗原的转录方面起着关键作用。AIRE基因的突变与严重的多器官自身免疫综合征(APECED)有关，AIRE缺陷小鼠的自身免疫反应性很明显。功能性AIRE蛋白表达为不同的核斑点，尽管没有结构基础来解释它们与疾病的相关性。在阐述APECED的细胞生物学基础时，我们有了一个意想不到的发现，即AIRE突变热点位于caspase募集域。结合同源建模和体外数据现在表明APECED突变是如何影响这种转录调节因子的活性的。我们还提供了新的体内证据，证明了AIRE与一个全球转录辅因子的关联，这可能是AIRE的转录组全基因组局部改变的基础。
Developing T cells encounter peripheral self-antigens in the thymus in order to delete autoreactive clones. It is now known that the autoimmune regulator protein ( AIRE), which is expressed in thymic medullary epithelial cells, plays a key role in regulating the thymic transcription of these peripheral tissue-specific antigens. Mutations in the AIRE gene are associated with a severe multiorgan autoimmune syndrome ( APECED), and autoimmune reactivities are manifest in AIRE-deficient mice. Functional AIRE protein is expressed as distinct nuclear puncta, although no structural basis existed to explain their relevance to disease. In addressing the cell biologic basis for APECED, we made the unexpected discovery that an AIRE mutation hot spot lies in a caspase recruitment domain. Combined homology modeling and in vitro data now show how APECED mutations influence the activity of this transcriptional regulator. We also provide novel in vivo evidence for AIRE's association with a global transcription cofactor, which may underlie AIRE's focal, genome-wide, alteration of the transcriptome.