ATP-sensitive potassium channels mediate survival during infection in mammals and insects
ATP-sensitive potassium channels mediate survival during infection in mammals and insects
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DOI：
10.1038/ng.2007.25
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发表时间：
2007-12-01
期刊：
影响因子：
30.8
通讯作者：
Beutler, Bruce
中科院分区：
文献类型：
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作者：
Croker, Ben;Crozat, Karine;Beutler, Bruce
特定的动态平衡机制赋予先天免疫反应稳定性，防止感染造成的伤害或死亡。在这里，我们从N-乙基-N-亚硝脲诱变小鼠的筛查中发现了一种突变，它既对小鼠巨细胞病毒感染具有极高的敏感性，又类似于对脂多糖(LPS)、聚(I.C)和免疫刺激(CpG)DNA的20,000倍敏化。导致内毒素反应的基因MyD88、Trif、TNF、Tnfrsf1a、Ifnb、IFNG或STAT1的突变并不抑制内毒素超敏表型，而是由造血细胞外在的异常引起的。这种表型是由于编码Kir6.1的Kcnj8的零等位基因所致，Kir6.1是一种与SUR2结合形成ATP敏感性钾通道(KATP)的蛋白，在冠状动脉平滑肌和内皮细胞中表达。在果蝇中，通过RNA干扰抑制dSUR类似地会引起对鸡舍病毒感染的超敏反应。因此，KATP在感染期间进化为一种稳态功能，在哺乳动物中，它可以防止依赖TLR和/或MDA5免疫受体的细胞因子诱导的冠状动脉血管收缩。
Specific homeostatic mechanisms confer stability in innate immune responses, preventing injury or death from infection. Here we identify, from a screen of N-ethyl-N-nitrosourea-mutagenized mice, a mutation causing both profound susceptibility to infection by mouse cytomegalovirus and similar to 20,000-fold sensitization to lipopolysaccharide ( LPS), poly( I. C) and immunostimulatory ( CpG) DNA. The LPS hypersensitivity phenotype is not suppressed by mutations in Myd88, Trif, Tnf, Tnfrsf1a, Ifnb, Ifng or Stat1, genes contributing to LPS responses, and results from an abnormality extrinsic to hematopoietic cells. The phenotype is due to a null allele of Kcnj8, encoding Kir6.1, a protein that combines with SUR2 to form an ATP-sensitive potassium channel ( KATP) expressed in coronary artery smooth muscle and endothelial cells. In Drosophila melanogaster, suppression of dSUR by RNA interference similarly causes hypersensitivity to infection by flock house virus. Thus, KATP evolved to serve a homeostatic function during infection, and in mammals it prevents coronary artery vasoconstriction induced by cytokines dependent on TLR and/ or MDA5 immunoreceptors.