与免疫反应相关的人的HIN-200家族包括4个成员,分别为黑色瘤缺乏因子2(absent in melanoma 2,AIM2)、MNDA、干扰素诱导蛋白16 (interferon-inducible protein 16,IFI16)和IFIX。其中,AIM2和IFI16分别是诱导炎性体形成和干扰素生成的DNA受体。
2012年4月5日,Immunity在线发表了美国国立健康研究院国家过敏症与传染病研究所(NIAID)等多家科研机构的一篇题为"Structures of the HIN Domain:DNA Complexes Reveal Ligand Binding and Activation Mechanisms of the AIM2 Inflammasome and IFI16 Receptor"的研究论文,解析了HIN结构域:DNA复合体的晶体结构。
在天然免疫中,DNA的识别对抗病毒和抗菌防御来说极为重要。结构显示, 通过带正电的HIN结构域残基和双链DNA的糖-磷酸骨架之间的静电吸引非特异性识别DNA序列。 自我抑制状态下,分子内热蛋白结构域和HIN结构域的复合体通过DNA的结合而分开, 这便于炎性体的装配。
这些发现为进一步理解天然信号复合体的装配机制提供了依据。(生物谷Bioon.com)
doi.org/10.1016/j.immuni.2012.02.014
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Structures of the HIN Domain:DNA Complexes Reveal Ligand Binding and Activation Mechanisms of the AIM2 Inflammasome and IFI16 Receptor
Tengchuan Jin1, Andrew Perry1, Jiansheng Jiang1, Patrick Smith1, James A. Curry1, Leonie Unterholzner2, Zhaozhao Jiang3, Gabor Horvath4, Vijay A. Rathinam3, Ricky W. Johnstone6, 7, Veit Hornung5, Eicke Latz3, 4, Andrew G. Bowie2, Katherine A. Fitzgerald3, T. Sam Xiao1, ,
1 Structural Immunobiology Unit, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892-0430, USA
2 School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland
3 Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA 01605, USA
4 Institute of Innate Immunity, University Hospitals, University of Bonn, 53127 Bonn, Germany
5 Unit for Clinical Biochemistry, Institute for Clinical Chemistry and Pharmacology, University Hospitals, University of Bonn, 53127 Bonn, Germany
6 Gene Regulation Laboratory, Cancer Therapeutics Program, The Peter MacCallum Cancer Institute, St. Andrews Place, East Melbourne 3002, Victoria, Australia
7 The Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville 3054, Victoria, Australia
Received 25 October 2011. Revised 23 December 2011. Accepted 9 February 2012. Available online 5 April 2012. Published online: April 5, 2012.
Summary
Recognition of DNA by the innate immune system is central to antiviral and antibacterial 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 mechanistic insights into dsDNA as the activation trigger and oligomerization platform for the assembly of large innate signaling complexes such as the inflammasomes.