Nature：最新细胞凋亡机制

　　

生物通报道，托马斯杰弗逊大学大学Kimmel癌症研究所细胞凋亡研究中心生物化学与分子生物学系的研究小组在细胞凋亡方面的研究取得新的进展，相关成果公布在1月22日Nature杂志上。

 

文章的通讯作者是研究细胞凋亡方面的专家Emad S. Alnemri教授，现任托马斯杰弗逊大学生化与分子生物学系教授，国内著名的科学家施一公曾与Emad S. Alnemri合作发表多篇细胞凋亡方面的文章。Emad S. Alnemri教授主要研究线粒体在细胞凋亡中所发挥的作用，以及Caspase在细胞凋亡中的调节作用。

 

在炎症反应中，病原体与宿主关联的胞质双链DNA可激发NALP3非依赖性的炎症因子，接下来激活Caspase诱导白细胞介素1β前体成熟，并促进炎症发生。在自然情况下，细胞质内的DNA所导致的炎症机制一直不明朗。

 

在本研究中，Emad S. Alnemri教授研究小组发现一种干扰素诱导的HIN-200家族蛋白AIM2（在黑色素瘤2细胞中缺乏），它在氨基端包含一个pyrin区域，而羧基末端包含一个寡核苷酸/低聚糖结合位点区。羧基端的寡核苷酸/低聚糖区能感知DNA（入侵的病原体的DNA）的存在，AIM2能通过pyrin区与ASC（apoptosis-associated speck-like protein containing a CARD）相互作用以激活Caspase。AIM2与ASC的相互作用还能介导生成ASC pyropotsome（该物质能诱导含有Caspase-1的细胞发生pyroptotic样的细胞凋亡）。用RNAi技术沉默掉AIM2可减少巨噬细胞因细胞质DNA引发的炎症反应，通常293T细胞在遭遇细胞质DNA后会持续表达AIM2。

 

研究结果表明，细胞质DNA可诱导AIM2寡聚化促使AIM2炎症反应复合物形成，表明AIM2是一个重要的炎症反应物，它可激活ASC pyroptosome和Caspase-1。（生物通 小茜）

 

生物通推荐原文：AIM2 activates the inflammasome and cell death in response to cytoplasmic DNA

 

【Abstract】

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.（生物通）