Structural basis for termination of AIM2-mediated signaling by p202  

作　　者：Heng Ru Xiangmin Ni LixiaZhao Christopher Crowle Wei Ding Li-Wei Hung Neil Shaw Genhong Cheng Zhi-Jie Liu 

机构地区：[1]National Laboratory of Biomacromolecules, Institute of Biophysics, Chi- nese Academy of Sciences, Beijing 100101, China [2]Department of Micro- biology, Immunology and Molecular Genetics, University of California Los Angeles, Los Angeles, CA 90095, USA [3]Institute of Molecular and Clinical Medicine, Kunming Medical University, Kunming 650500, China, [4]physics Division, Los Alamos National Laboratory, Los Alamos, NM87545, USA

出　　处：《Cell Research》2013年第6期855-858,共4页细胞研究（英文版）

摘　　要：Sighting and binding of double-stranded DNA （ds- DNA） by a sensor in the cytoplasm trigger the activation of the immune-surveillance pathways [1]. The crystal structure of absent in melanoma 2 （AIM2） bound with DNA conclusively defines the role of AIM2 as a sensor in the innate immune system [2]. AIM2 belongs to the PYHIN family of proteins and contains a pyrin domain （PYD） followed by a hematopoietic interferon-inducible nuclear protein （HIN） domain （Figure 1A）. AIM2 binds DNA via the HIN domain and recruits the adaptor pro- tein apoptosis-associated speck-like protein containing a caspase recruitment domain （ASC） via the PYD. ASC in turn recruits caspase-1 via CARD-CARD interaction, resulting in the formation of inflammasomes comprised of AIM2, ASC and caspase-1. The molecular crowding of the AIM2 inflammasome ensures the proteolysis and transactivation of caspase-1. Activated caspase-1 cleaves pro-IL-1 ]3 and pro-IL-18 into their mature proinflamma- tory forms [3, 4]. The termination of inflammatory responses originated from inflammasomes can be accomplished by employing naturally occurring dominant-negative antagonists [4]. Dominant-negative proteins are similar to their canoni- cal counterparts except for a missing effector domain, so that they cannot relay the signals any further. They out- compete their canonical counterparts for ligands or bind- ing sites and thus block the downstream signal transduc- tion. Such regulation is essential for maintaining cellular homeostasis. To regulate inflammasome activation, mice have evolved a strategy that has so far not been discov- ered in humans. Mice use the H1N-only protein, p202, to sequester cytoplasmic dsDNA and render it unavailable for its canonical sensor, AIM2 [4]. p202 contains two HIN domains （HINa and H1Nb）, but lacks the PYD （Fig- ure 1A）. Therefore, p202 is unable to recruit the adaptor ASC, and its binding to DNA results in the termination of inflammasome signaling. The significance of p202 in the regulation of the inn

关 键 词：信号转导机制 结构基础 介导 双链DNA 蛋白质家族 CASPASE 系统性红斑狼疮 螺旋结构 

分 类 号：Q257[生物学—细胞生物学] TU391[建筑科学—结构工程]