【进展】启动炎症反应的DNA传感器——AIM2
丁香园论坛
1621
Nature Immunology,Advanced online publications,Published online: 21 January 2009.
An orthogonal proteomic-genomic screen identifies AIM2 as a cytoplasmic DNA sensor for the inflammasome
Tilmann Bürckstümmer, Christoph Baumann, et al.
Cytoplasmic DNA triggers activation of the innate immune system. Although 'downstream' signaling components have been characterized, the DNA-sensing components remain elusive. Here we present a systematic proteomics screen for proteins that associate with DNA, 'crossed' to a screen for transcripts induced by interferon-, which identified AIM2 as a candidate cytoplasmic DNA sensor. AIM2 showed specificity for double-stranded DNA. It also recruited the inflammasome adaptor ASC and localized to ASC 'speckles'. A decrease in AIM2 expression produced by RNA-mediated interference impaired DNA-induced maturation of interleukin 1 in THP-1 human monocytic cells, which indicated that endogenous AIM2 is required for DNA recognition. Reconstitution of unresponsive HEK293 cells with AIM2, ASC, caspase-1 and interleukin 1 showed that AIM2 was sufficient for inflammasome activation. Our data suggest that AIM2 is a cytoplasmic DNA sensor for the inflammasome.
内容简介
病毒感染可触发固有免疫应答。在很多情况下，机体通过模式识别受体（PRR）识别病毒基因组或者病毒复制中间体的核苷酸序列探测侵入的病毒。现在已经知道少数几类核苷酸受体，例如Toll样3,7,8,9识别胞内膜成分，RIG-I家族中的RNA结螺旋酶在胞浆中发挥作用。胞质中DNA的识别机制尚不清楚，目前认为是通过DAI（DLM-1或ZBPI）介导。同时，人们还坚信胞质中存在未知的DNA传感器分子(Cytoplastic DNA sensors)参与胞质DNA的识别，启动下游免疫应答。
本文的作者采用蛋白质组-基因组正交筛选方法（这个方法没有完全理解，请达人指点），确认了一个识别胞质中双链DNA的胞质蛋白AIM2(absent in melanoma 2,UniProt accession number,O14862)，并证实该蛋白通过ASC-Caspase1途径，促进IL-1beta成熟，活化炎症复合体(inflammasome)。
另外，基因分析发现，AIM2编码基因位于SLE易感性基因座内部，提示AIM2高表达或者高活性与SLE发生密切相关。结肠癌组织中发现AIM2编码基因缺失或突变，提示在特定癌症类型中，AIM2可能发挥保护作用。
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An orthogonal proteomic-genomic screen identifies AIM2 as a cytoplasmic DNA sensor for the inflammasome
Tilmann Bürckstümmer, Christoph Baumann, et al.
Cytoplasmic DNA triggers activation of the innate immune system. Although 'downstream' signaling components have been characterized, the DNA-sensing components remain elusive. Here we present a systematic proteomics screen for proteins that associate with DNA, 'crossed' to a screen for transcripts induced by interferon-, which identified AIM2 as a candidate cytoplasmic DNA sensor. AIM2 showed specificity for double-stranded DNA. It also recruited the inflammasome adaptor ASC and localized to ASC 'speckles'. A decrease in AIM2 expression produced by RNA-mediated interference impaired DNA-induced maturation of interleukin 1 in THP-1 human monocytic cells, which indicated that endogenous AIM2 is required for DNA recognition. Reconstitution of unresponsive HEK293 cells with AIM2, ASC, caspase-1 and interleukin 1 showed that AIM2 was sufficient for inflammasome activation. Our data suggest that AIM2 is a cytoplasmic DNA sensor for the inflammasome.
内容简介
病毒感染可触发固有免疫应答。在很多情况下，机体通过模式识别受体（PRR）识别病毒基因组或者病毒复制中间体的核苷酸序列探测侵入的病毒。现在已经知道少数几类核苷酸受体，例如Toll样3,7,8,9识别胞内膜成分，RIG-I家族中的RNA结螺旋酶在胞浆中发挥作用。胞质中DNA的识别机制尚不清楚，目前认为是通过DAI（DLM-1或ZBPI）介导。同时，人们还坚信胞质中存在未知的DNA传感器分子(Cytoplastic DNA sensors)参与胞质DNA的识别，启动下游免疫应答。
本文的作者采用蛋白质组-基因组正交筛选方法（这个方法没有完全理解，请达人指点），确认了一个识别胞质中双链DNA的胞质蛋白AIM2(absent in melanoma 2,UniProt accession number,O14862)，并证实该蛋白通过ASC-Caspase1途径，促进IL-1beta成熟，活化炎症复合体(inflammasome)。
另外，基因分析发现，AIM2编码基因位于SLE易感性基因座内部，提示AIM2高表达或者高活性与SLE发生密切相关。结肠癌组织中发现AIM2编码基因缺失或突变，提示在特定癌症类型中，AIM2可能发挥保护作用。
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