Augmentation of CFTR maturation by S-nitrosoglutathione reductase.
Augmentation of CFTR maturation by S-nitrosoglutathione reductase.
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DOI：
10.1152/ajplung.00269.2014
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发表时间：
2016-02
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通讯作者：
K. Zaman;Victoria Sawczak;Atiya Zaidi;Maya Butler;Deric Bennett;Paulina M. Getsy;Maryam Zeinomar;Zivi Greenberg;M. Forbes;Shagufta Rehman;Vinod Jyothikumar;Kimberly Deronde;A. Sattar;Laura Smith;Deborah A. Corey;A. Straub;F. Sun;L. Palmer;A. Periasamy;S. Randell;T. Kelley;S. Lewis;B. Gaston
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作者：
K. Zaman;Victoria Sawczak;Atiya Zaidi;Maya Butler;Deric Bennett;Paulina M. Getsy;Maryam Zeinomar;Zivi Greenberg;M. Forbes;Shagufta Rehman;Vinod Jyothikumar;Kimberly Deronde;A. Sattar;Laura Smith;Deborah A. Corey;A. Straub;F. Sun;L. Palmer;A. Periasamy;S. Randell;T. Kelley;S. Lewis;B. Gaston
S-亚硝基谷胱甘肽 (GSNO) 还原酶调节新型内源性 S-亚硝基硫醇信号通路，缺乏 GSNO 还原酶的小鼠可以免受气道高反应性的影响。 S-亚硝基硫醇存在于气道中，囊性纤维化 (CF) 患者的 S-亚硝基硫醇水平往往较低，这可能是由于 GSNO 还原酶活性上调所致。本研究表明：1) 与野生型 CFBE41o(-) 细胞相比，表达突变型 F508del-囊性纤维化跨膜调节因子 (CFTR) 的囊性纤维化支气管上皮 (CFBE41o(-)) 细胞中 GSNO 还原酶活性增加，2) 与野生型 CFBE41o(-) 细胞相比，表达突变型 F508del-CFTR 的原代人支气管上皮细胞中 GSNO 还原酶表达水平增加野生型细胞，3) GSNO 还原酶与人气道上皮细胞中的辅助伴侣 Hsp70/Hsp90 组织蛋白 (Hop; Stip1) 共定位，4) GSNO 还原酶敲低与 siRNA 增加 CFTR 的表达和成熟，并减少人气道上皮细胞中的 Stip1 表达，5) GSNO 还原酶水平增加导致 CFTR 成熟减少，6) GSNO还原酶抑制剂可有效逆转 GSNO 还原酶对 CFTR 成熟的影响。这些研究提供了一种新的方法来定义 Stip1 和 GSNO 还原酶之间相互作用的亚细胞位置以及 S-亚硝基硫醇在这些相互作用中的作用。
S-nitrosoglutathione (GSNO) reductase regulates novel endogenous S-nitrosothiol signaling pathways, and mice deficient in GSNO reductase are protected from airways hyperreactivity. S-nitrosothiols are present in the airway, and patients with cystic fibrosis (CF) tend to have low S-nitrosothiol levels that may be attributed to upregulation of GSNO reductase activity. The present study demonstrates that 1) GSNO reductase activity is increased in the cystic fibrosis bronchial epithelial (CFBE41o(-)) cells expressing mutant F508del-cystic fibrosis transmembrane regulator (CFTR) compared with the wild-type CFBE41o(-) cells, 2) GSNO reductase expression level is increased in the primary human bronchial epithelial cells expressing mutant F508del-CFTR compared with the wild-type cells, 3) GSNO reductase colocalizes with cochaperone Hsp70/Hsp90 organizing protein (Hop; Stip1) in human airway epithelial cells, 4) GSNO reductase knockdown with siRNA increases the expression and maturation of CFTR and decreases Stip1 expression in human airway epithelial cells, 5) increased levels of GSNO reductase cause a decrease in maturation of CFTR, and 6) a GSNO reductase inhibitor effectively reverses the effects of GSNO reductase on CFTR maturation. These studies provide a novel approach to define the subcellular location of the interactions between Stip1 and GSNO reductase and the role of S-nitrosothiols in these interactions.