美國(guó)托馬斯杰弗遜大學(xué)大學(xué)Kimmel癌癥研究所細(xì)胞凋亡研究中心生物化學(xué)與分子生物學(xué)系的研究小組在細(xì)胞凋亡方面的研究取得新的進(jìn)展,，相關(guān)成果公布在1月22日Nature雜志上,。
在炎癥反應(yīng)中,，病原體與宿主關(guān)聯(lián)的胞質(zhì)雙鏈DNA可激發(fā)NALP3非依賴性的炎癥因子，接下來激活Caspase誘導(dǎo)白細(xì)胞介素1β前體成熟,，并促進(jìn)炎癥發(fā)生,。在自然情況下，細(xì)胞質(zhì)內(nèi)的DNA所導(dǎo)致的炎癥機(jī)制一直不明朗,。
在本研究中,，Emad S. Alnemri教授研究小組發(fā)現(xiàn)一種干擾素誘導(dǎo)的HIN-200家族蛋白AIM2（在黑色素瘤2細(xì)胞中缺乏），它在氨基端包含一個(gè)pyrin區(qū)域,，而羧基末端包含一個(gè)寡核苷酸/低聚糖結(jié)合位點(diǎn)區(qū),。羧基端的寡核苷酸/低聚糖區(qū)能感知DNA（入侵的病原體的DNA）的存在，AIM2能通過pyrin區(qū)與ASC（apoptosis-associated speck-like protein containing a CARD）相互作用以激活Caspase,。AIM2與ASC的相互作用還能介導(dǎo)生成ASC pyropotsome（該物質(zhì)能誘導(dǎo)含有Caspase-1的細(xì)胞發(fā)生pyroptotic樣的細(xì)胞凋亡）,。用RNAi技術(shù)沉默掉AIM2可減少巨噬細(xì)胞因細(xì)胞質(zhì)DNA引發(fā)的炎癥反應(yīng)，通常293T細(xì)胞在遭遇細(xì)胞質(zhì)DNA后會(huì)持續(xù)表達(dá)AIM2,。
研究結(jié)果表明,，細(xì)胞質(zhì)DNA可誘導(dǎo)AIM2寡聚化促使AIM2炎癥反應(yīng)復(fù)合物形成，表明AIM2是一個(gè)重要的炎癥反應(yīng)物,，它可激活A(yù)SC pyroptosome和Caspase-1,。（生物谷Bioon.com）
生物谷推薦原始出處：
Nature advance online publication 21 January 2009 | doi:10.1038/nature07710
AIM2 activates the inflammasome and cell death in response to cytoplasmic DNA
Teresa Fernandes-Alnemri1,2, Je-Wook Yu1,2, Pinaki Datta1, Jianghong Wu1 & Emad S. Alnemri1
1 Department of Biochemistry and Molecular Biology, Center for Apoptosis Research, Kimmel Cancer Institute, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA
2 These authors contributed equally to this work.
Host- and pathogen-associated cytoplasmic double-stranded DNA triggers the activation of a NALP3 (also known as cryopyrin and NLRP3)-independent inflammasome1, which activates caspase-1 leading to maturation of pro-interleukin-1 and inflammation. The nature of the cytoplasmic-DNA-sensing inflammasome is currently unknown. Here we show that AIM2 (absent in melanoma 2), an interferon-inducible HIN-200 family member that contains an amino-terminal pyrin domain and a carboxy-terminal oligonucleotide/oligosaccharide-binding domain2, 3, senses cytoplasmic DNA by means of its oligonucleotide/oligosaccharide-binding domain and interacts with ASC (apoptosis-associated speck-like protein containing a CARD) through its pyrin domain to activate caspase-1. The interaction of AIM2 with ASC also leads to the formation of the ASC pyroptosome4, which induces pyroptotic cell death in cells containing caspase-1. Knockdown of AIM2 by short interfering RNA reduced inflammasome/pyroptosome activation by cytoplasmic DNA in human and mouse macrophages, whereas stable expression of AIM2 in the non-responsive human embryonic kidney 293T cell line conferred responsiveness to cytoplasmic DNA. Our results show that cytoplasmic DNA triggers formation of the AIM2 inflammasome by inducing AIM2 oligomerization. This study identifies AIM2 as an important inflammasome component that senses potentially dangerous cytoplasmic DNA, leading to activation of the ASC pyroptosome and caspase-1.
