CFTR is a pattern recognition molecule that extracts Pseudomonas aeruginosa LPS from the outer membrane into epithelial cells and activates NF-κB translocation
CFTR is a pattern recognition molecule that extracts Pseudomonas aeruginosa LPS from the outer membrane into epithelial cells and activates NF-κB translocation
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DOI：
10.1073/pnas.092160899
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发表时间：
2002-05-14
影响因子：
11.1
通讯作者：
Pier, GB
中科院分区：
文献类型：
--
作者：
Schroeder, TH;Lee, MM;Pier, GB
免疫细胞在对抗原的细胞反应中通过两种机制被激活：(i)直接摄取抗原和（ii）从抗原呈递细胞中提取和内化膜成分。虽然模式识别分子（PRM）对微生物抗原的内吞作用也能激活先天免疫，但尚不清楚这是否涉及微生物表面成分的提取和内化。粘膜表面的上皮细胞使用不同于经典内吞PRM的多种受体来结合和内化完整的微生物。非经典受体分子理论上可以作为一种内吞PRM，如果这些分子能够识别、结合、提取和内化病原体相关分子并启动细胞信号传导。我们在此报道，囊性纤维化跨膜传导调节剂（CFTR）与铜绿假单胞菌外膜脂多糖（LPS）的外核寡糖之间的相互作用满足所有这些条件。P. aeruginosa LPS被CFTR特异性识别并结合，从生物体表面提取，并被上皮细胞内吞，导致核转录因子NF-kappaB快速（5- 15分钟）辅助动态易位。抑制P. aeruginosa LIPS的上皮细胞内化可阻止NF-kappaB的激活。细胞活化依赖于野生型CFTR的表达，因为培养的DeltaF508 CFTR人气道上皮细胞和转基因cf小鼠肺上皮细胞都不能内吞LPS和转运NF-kappaB。CFTR在肺上皮中作为一个关键的内吞PRM，协调对铜绿假单胞菌感染的有效先天免疫反应。
immune cells are activated during cellular responses to antigen by two described mechanisms: (i) direct uptake of antigen and (ii) extraction and internalization of membrane components from antigen-presenting cells. Although endocytosis of microbial antigens by pattern recognition molecules (PRM) also activates innate immunity, it is not known whether this involves extraction and internalization of microbial surface components. Epithelial cells on mucosal surfaces use a variety of receptors that are distinct from the classical endocytic PRM to bind and internalize intact microorganisms. Nonclassical receptor molecules theoretically could act as a type of endocytic PRM if these molecules could recognize, bind, extract, and internalize a pathogen-associated molecule an initiate cell signaling. We report here that the interaction between the cystic fibrosis transmembrane conductance regulator (CFTR) an the outer core oligosaccharide of the lipopolysaccharide (LPS) in the outer membrane of Pseudomonas aeruginosa satisfies all of these conditions. P. aeruginosa LPS was specifically recognized and bound by CFTR, extracted from the organism's surface, and endocytosed by epithelial cells, leading to a rapid (5- to 15-min) aid dynamic translocation of nuclear transcription factor NF-kappaB. Inhibition of epithelial cell internalization of P. aeruginosa LIPS prevented NF-kappaB activation. Cellular activation depended on expression of wild-type CFTR, because both cultured DeltaF508 CFTR human airway epithelial cells and lung epithelial cells of transgenic-CF mice failed to endocytose LPS and translocate NF-kappaB. CFTR serves as a critical endocytic PRM in the lung epithelium, coordinating the effective innate immune response to A aeruginosa infection.