Science：Caspase活性机制新发现

　　

生物通报道，澳大利亚昆士兰大学也分子生物科学系，放射生物学与肿瘤学实验室的研究者研究Caspase活性获得新突破，最新成果结论发表在1月份的Science杂志上。

 

Caspases是近年来发现的一组存在于胞质溶胶中的结构上相关的半胱氨酸蛋白酶，它们的一个重要共同点是特异地断开天冬氨酸残基后的肽键。Caspase能够高度选择性地切割某些蛋白质，这种切割只发生在少数（通常只有1个）位点上，主要是在结构域间的位点上，切割的结果或是活化某种蛋白，或使某种蛋白失活，但从不完全降解一种蛋白质。

 

外源性的核酸能激活哺乳动物的天然免疫应答反应。一旦探测到细胞质中存在有外源性的双链DNA（double stranded DNA），免疫系统就会开始工作激起特异性的抗病毒应答和巨噬细胞死亡活动。细胞质里的双链DNA能快速激活骨髓衍生的巨噬细胞中的Caspase3和Caspase1酶。

 

在本研究中，研究人员发现HIN-200家族成员和lupus susceptibility factor，p202是双链DNA的结合蛋白，能稳定并快速地转染DNA。研究者敲除p202表达基因，研究p202的功能，结果发现p202是DNA诱导Caspase激活反应的抑制因子。而相反的是，HIN200因子和AIM2（p210）是细胞质激活Caspase的激动剂。这些研究结果表明，HIN-200蛋白家族是细胞质外源双链DNA介导的Caspase活化反应的识别启动因子。

 

生物通 小茜

原文检索：HIN-200 Proteins Regulate Caspase Activation in Response to Foreign Cytoplasmic DNA

Tara L. Roberts 1, Adi Idris 2, Jasmyn A. Dunn 2, Greg M. Kelly 2, Carol M. Burnton 2, Samantha Hodgson 2, Lani L. Hardy 2, Valerie Garceau 3, Matthew J. Sweet 4, Ian L. Ross 2, David A. Hume 3, Katryn J. Stacey 4*

1 The University of Queensland, Institute for Molecular Bioscience, Qld 4072, Australia.; Present address: Radiation Biology and Oncology Laboratory, Queensland Institute of Medical Research, Brisbane, QLD 4029, Australia.

2 The University of Queensland, Institute for Molecular Bioscience, Qld 4072, Australia.

3 The University of Queensland, Institute for Molecular Bioscience, Qld 4072, Australia.; Present Address: The Roslin Institute, University of Edinburgh, Roslin EH259PS, Scotland, UK.

4 The University of Queensland, School of Chemistry and Biomolecular Science, Qld 4072, Australia.

【Abstract】

The mammalian innate immune system is activated by foreign nucleic acids. Detection of double-stranded DNA (dsDNA) in the cytoplasm triggers characteristic antiviral responses and macrophage cell death. Cytoplasmic dsDNA rapidly activated caspase 3 and caspase 1 in bone marrow-derived macrophages. We identified the HIN-200 family member and lupus susceptibility factor, p202, as a dsDNA binding protein that bound stably and rapidly to transfected DNA. Knockdown studies identified p202 as an inhibitor of DNA-induced caspase activation. Conversely, the related pyrin domain-containing HIN-200 factor, AIM2 (p210), was required for caspase activation by cytoplasmic dsDNA. This work indicates that HIN-200 proteins can act as pattern recognition receptors mediating responses to cytoplasmic dsDNA.