Elevated furin levels in human cystic fibrosis cells result in hypersusceptibility to exotoxin A-induced cytotoxicity
Elevated furin levels in human cystic fibrosis cells result in hypersusceptibility to exotoxin A-induced cytotoxicity
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DOI：
10.1172/jci31499
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发表时间：
2007-11-01
影响因子：
15.9
通讯作者：
Deretic, Vojo
中科院分区：
文献类型：
--
作者：
Ornatowski, Wojciech;Poschet, Jens F.;Deretic, Vojo
进行性肺部疾病和铜绿假单胞菌感染仍然是囊性纤维化（CF）的一个棘手问题。在细胞水平上，CF的特征在于细胞器过度酸化，这导致蛋白质和脂质糖基化改变。改变反式高尔基体网络（TGN）的pH值可能会进一步破坏发生在这个细胞器中的蛋白质加工和包装。在这里，我们测量了主要的TGN内切蛋白酶弗林蛋白酶的活性，并证明了在人CF细胞中的显著上调。弗林蛋白酶活性增加与CF中免疫抑制和组织重塑细胞因子TGF-β及其下游效应（包括巨噬细胞失活和上皮细胞胶原分泌增加）的产生增加有关。由于弗林蛋白酶负责一系列内源性和外源性底物（包括生长因子和细菌毒素）的蛋白水解加工，因此我们确定，与遗传匹配的CF跨膜电导调节因子校正细胞相比，外毒素A的弗林蛋白酶依赖性激活升高导致CF呼吸道上皮细胞的细胞死亡增加。因此，CF呼吸道上皮细胞中弗林蛋白酶水平升高有助于细菌毒素诱导的细胞死亡、纤维化和局部免疫抑制。这些数据表明，弗林蛋白酶抑制剂的使用可能代表CF的药物治疗策略。
Progressive pulmonary disease and infections with Pseudomonas aeruginosa remain an intractable problem in cystic fibrosis (CF). At the cellular level, CF is characterized by organellar hyperacidification, which results in altered protein and lipid glycosylation. Altered pH of the trans-Golgi network (TGN) may further disrupt the protein processing and packaging that occurs in this organelle. Here we measured activity of the major TGN endoprotease furin and demonstrated a marked upregulation in human CF cells. Increased furin activity was linked to elevated production in CF of the immunosuppressive and tissue remodeling cytokine TGF-beta and its downstream effects, including macrophage deactivation and augmented collagen secretion by epithelial cells. As furin is responsible for the proteolytic processing of a range of endogenous and exogenous substrates including growth factors and bacterial toxins, we determined that elevated furin-dependent activation of exotoxin A caused increased cell death in CF respiratory epithelial cells compared with genetically matched CF transmembrane conductance regulator-corrected cells. Thus elevated furin levels in CF respiratory epithelial cells contributes to bacterial toxin-induced cell death, fibrosis, and local immunosuppression. These data suggest that the use of furin inhibitors may represent a strategy for pharmacotherapy in CF.