Structural basis for termination of AIM2-mediated signaling by p202

• Published in: Cell research 2013-06, Vol.23 (6), p.855-858
• Main Authors: Ru, Heng, Ni, Xiangmin, Zhao, Lixia, Crowley, Christopher, Ding, Wei, Hung, Li-Wei, Shaw, Neil, Cheng, Genhong, Liu, Zhi-Jie
• Format: Article
• Language: English
• Subjects: 631/250/256/2177; 631/45/147; 631/535; 631/80/86; Amino Acid Sequence; Animals; Biomedical and Life Sciences; caspase; Caspase 1 - metabolism; Cell Biology; Crystallography, X-Ray; DNA-Binding Proteins - metabolism; Enzyme Activation; Intracellular Signaling Peptides and Proteins - metabolism; Letter to the Editor; Life Sciences; Mice; Nuclear Proteins - metabolism; Nuclear Proteins - ultrastructure; Protein Structure, Tertiary; Sequence Alignment; Signal Transduction; 介导; 信号转导机制; 双链DNA; 系统性红斑狼疮; 结构基础; 蛋白质家族; 螺旋结构
• ISSN: 1001-0602; 1748-7838
• DOI: 10.1038/cr.2013.52

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 innate immune responses is exem- plified by the fact that dysregulation of p202 function hasbeen linked to increased susceptibility to systemic lupus erythematosus [5]. To more clearly understand the mechanism of inhibi- tion of AIM2-mediated signaling by p202, it is essential to solve the structure of p202 in complex with DNA and compare it with that of AIM2 complexed with DNA. p202 has so far only been detected in mice. To compare the structure of AIM2 and p202 from the same specie