Yoshida Hideyuki, Bansal Kushagra, Schaefer Uwe, Chapman Trevor, Rioja Inmaculada, Proekt Irina, Anderson Mark S, Prinjha Rab K, Tarakhovsky Alexander, Benoist Christophe, Mathis Diane
Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115;
Laboratory of Immune Cell Epigenetics and Signaling, The Rockefeller University, New York, NY 10065;
Proc Natl Acad Sci U S A. 2015 Aug 11;112(32):E4448-57. doi: 10.1073/pnas.1512081112. Epub 2015 Jul 27.
Aire controls immunologic tolerance by inducing a battery of thymic transcripts encoding proteins characteristic of peripheral tissues. Its unusually broad effect is achieved by releasing RNA polymerase II paused just downstream of transcriptional start sites. We explored Aire's collaboration with the bromodomain-containing protein, Brd4, uncovering an astonishing correspondence between those genes induced by Aire and those inhibited by a small-molecule bromodomain blocker. Aire:Brd4 binding depended on an orchestrated series of posttranslational modifications within Aire's caspase activation and recruitment domain. This interaction attracted P-TEFb, thereby mobilizing downstream transcriptional elongation and splicing machineries. Aire:Brd4 association was critical for tolerance induction, and its disruption could account for certain point mutations that provoke human autoimmune disease. Our findings evoke the possibility of unanticipated immunologic mechanisms subtending the potent antitumor effects of bromodomain blockers.
Aire通过诱导一系列编码外周组织特征性蛋白质的胸腺转录本来控制免疫耐受。它异常广泛的作用是通过释放恰好在转录起始位点下游暂停的RNA聚合酶II来实现的。我们探究了Aire与含溴结构域蛋白Brd4的协作关系，发现Aire诱导的基因与小分子溴结构域阻断剂抑制的基因之间存在惊人的对应关系。Aire:Brd4结合依赖于Aire的半胱天冬酶激活和募集结构域内一系列精心编排的翻译后修饰。这种相互作用吸引了P-TEFb，从而调动下游转录延伸和剪接机制。Aire:Brd4关联对于耐受诱导至关重要，其破坏可能解释某些引发人类自身免疫性疾病的点突变。我们的发现引发了这样一种可能性，即存在意想不到的免疫机制支撑着溴结构域阻断剂强大的抗肿瘤作用。
