Structures of the HIN domain:DNA complexes reveal ligand binding and activation mechanisms of the AIM2 inflammasome and IFI16 receptor.
Structures of the HIN domain:DNA complexes reveal ligand binding and activation mechanisms of the AIM2 inflammasome and IFI16 receptor.
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DOI：
10.1016/j.immuni.2012.02.014
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发表时间：
2012-04-20
期刊：
影响因子：
32.4
通讯作者：
Xiao TS
中科院分区：
文献类型：
--
作者：
Jin T;Perry A;Jiang J;Smith P;Curry JA;Unterholzner L;Jiang Z;Horvath G;Rathinam VA;Johnstone RW;Hornung V;Latz E;Bowie AG;Fitzgerald KA;Xiao TS
先天免疫系统对DNA的识别是抗病毒和抗细菌防御的核心，也是涉及自身DNA的自身免疫性疾病的重要因素。AIM2(在黑色素瘤2中缺失)和IFI16(干扰素诱导蛋白16)分别被确定为诱导炎症体形成和干扰素产生的DNA受体。在这里，我们介绍了他们的HIN结构域与双链(DS)DNA络合物的晶体结构。非序列特异性DNA识别是通过带正电荷的HIN结构域残基和dsDNA糖-磷酸骨架之间的静电吸引来完成的。DNA结合释放了自身抑制状态的AIM2PYRIN和HIN结构域的分子内复合体，这可能有助于沿着DNA阶梯组装炎性小体。这些发现为dsDNA作为大的天然信号复合体(如炎性小体)组装的激活触发和寡聚平台提供了新的机制见解。
Recognition of DNA by the innate immune system is central to anti-viral and anti-bacterial defenses, as well as an important contributor to autoimmune diseases involving self DNA. AIM2 (absent in melanoma 2) and IFI16 (interferon-inducible protein 16) have been identified as DNA receptors that induce inflammasome formation and interferon production, respectively. Here we present the crystal structures of their HIN domains in complex with double-stranded (ds) DNA. Non-sequence specific DNA recognition is accomplished through electrostatic attraction between the positively charged HIN domain residues and the dsDNA sugar-phosphate backbone. An intramolecular complex of the AIM2 Pyrin and HIN domains in an autoinhibited state is liberated by DNA binding, which may facilitate the assembly of inflammasomes along the DNA staircase. These findings provide novel mechanistic insights into dsDNA as the activation trigger and oligomerization platform for the assembly of large innate signaling complexes such as the inflammasomes.
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