Hsp 70/Hsp 90 organizing protein as a nitrosylation target in cystic fibrosis therapy

Nadzeya V. Marozkina; Sean Yemen; Molly Borowitz; Lei Liu; Melissa Plapp; Fei Sun; Rafique lslam; Petra Erdmann-Gilmore; R. Reid Townsend; Cheryl F. Lichti; Sneha Mantri; Phillip W. Clapp; Scott H. Randell; Benjamin Gaston; Khalequz Zaman

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Hsp 70/Hsp 90 organizing protein as a nitrosylation target in cystic fibrosis therapy

机译：Hsp 70 / Hsp 90组织蛋白在囊性纤维化治疗中作为亚硝化靶标

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摘要

The endogenous signaling molecule S-nitrosoglutathione (GSNO) and other S-nitrosylating agents can cause full maturation of the abnormal gene product △F508 cystic fibrosis (CF) transmembrane conductance regulator (CFTR). However, the molecular mechanism of action is not known. Here we show that Hsp70/Hsp90 organizing protein (Hop) is a critical target of GSNO, and its S-nitrosylation results in AF508 CFTR maturation and cell surface expression. S-nitrosylation by GSNO inhibited the association of Hop with CFTR in the endoplasmic reticulum. This effect was necessary and sufficient to mediate GSNO-induced cell-surface expression of △F508 CFTR. Hop knockdown using siRNA recapitulated the effect of GSNO on △F508 CFTR maturation and expression. Moreover, GSNO acted additively with decreased temperature, which promoted mutant CFTR maturation through a Hop-independent mechanism. We conclude that GSNO corrects △F508 CFTR trafficking by inhibiting Hop expression, and that combination therapies-using differing mechanisms of action-may have additive benefits in treating CF.

机译：内源性信号分子S-亚硝基谷胱甘肽（GSNO）和其他S-亚硝基化剂可导致异常基因产物△F508囊性纤维化（CF）跨膜电导调节剂（CFTR）完全成熟。然而，作用的分子机理尚不清楚。在这里，我们显示Hsp70 / Hsp90组织蛋白（Hop）是GSNO的关键目标，其S-亚硝基化可导致AF508 CFTR成熟和细胞表面表达。 GSNO进行的S-亚硝基化抑制了内质网中Hop与CFTR的结合。该作用对于介导GSNO诱导的△F508 CFTR的细胞表面表达是必要和充分的。使用siRNA进行的蛇麻草敲除可以概括GSNO对△F508 CFTR成熟和表达的影响。此外，GSNO在降低的温度下具有加性作用，这通过独立于Hop的机制促进了突变体CFTR的成熟。我们得出的结论是，GSNO通过抑制Hop表达来纠正△F508 CFTR转运，并且使用不同作用机制的联合疗法在治疗CF中可能具有附加益处。

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来源
《Proceedings of the National Academy of Sciences of the United States of America》 |2010年第25期|P.11393-11398|共6页
作者
Nadzeya V. Marozkina; Sean Yemen; Molly Borowitz; Lei Liu; Melissa Plapp; Fei Sun; Rafique lslam; Petra Erdmann-Gilmore; R. Reid Townsend; Cheryl F. Lichti; Sneha Mantri; Phillip W. Clapp; Scott H. Randell; Benjamin Gaston; Khalequz Zaman;
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作者单位

Department of Pediatric Respiratory Medicine, University of Virginia School of Medicine, Charlottesville, VA 22908;

rnDepartment of Pediatric Respiratory Medicine, University of Virginia School of Medicine, Charlottesville, VA 22908;

rnDepartment of Pediatric Respiratory Medicine, University of Virginia School of Medicine, Charlottesville, VA 22908;

rnDepartment of Public Health Sciences, University of Virginia School of Medicine, Charlottesville, VA 22908;

rnDepartment of Pediatric Respiratory Medicine, University of Virginia School of Medicine, Charlottesville, VA 22908;

rnDepartment of Cell Biology and Physiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261;

rnDepartment of Biochemistry and Biophysics, Texas A&M University, College Station, TX 77843;

rnWashington University Proteomics Center, St. Louis, MO 63108-2259;

rnWashington University Proteomics Center, St. Louis, MO 63108-2259;

rnWashington University Proteomics Center, St. Louis, MO 63108-2259;

rnDepartment of Pediatric Respiratory Medicine, University of Virginia School of Medicine, Charlottesville, VA 22908;

rnDepartment of Medicine, University of North Carolina, Chapel Hill, NC 27599;

rnDepartment of Medicine, University of North Carolina, Chapel Hill, NC 27599;

rnDepartment of Pediatric Respiratory Medicine, University of Virginia School of Medicine, Charlottesville, VA 22908;

rnDepartment of Pediatric Respiratory Medicine, University of Virginia School of Medicine, Charlottesville, VA 22908;

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收录信息美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
原文格式 PDF
正文语种 eng
中图分类
关键词
cystic fibrosis transmembrane conductance regulator; S-nitrosoglutathione corrector I treatment;

机译：囊性纤维化跨膜电导调节剂S-亚硝基谷胱甘肽校正剂I治疗;

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1. Y-632 inhibits heat shock protein 90 (Hsp90) function by disrupting the interaction between Hsp90 and Hsp70/Hsp90 organizing protein, and exerts antitumor activity in vitro and in vivo [J] . Wang Wenqian, Liu Yang, Zhao Zhixin, Cancer science. . 2016,第6期

机译：Y-632通过破坏Hsp90和Hsp70 / Hsp90组织蛋白之间的相互作用来抑制热休克蛋白90（Hsp90）的功能，并在体内和体外发挥抗肿瘤活性
2. Y‐632 inhibits heat shock protein 90 (Hsp90) function by disrupting the interaction between Hsp90 and Hsp70/Hsp90 organizing protein, and exerts antitumor activity in vitro and in vivo [J] . Cancer science. . 2016,第6期

机译：Y‐632通过破坏Hsp90和Hsp70 / Hsp90组织蛋白之间的相互作用来抑制热休克蛋白90（Hsp90）功能，并在体内和体外发挥抗肿瘤活性
3. Y-632 inhibits heat shock protein 90 (Hsp90) function by disrupting the interaction between Hsp90 and Hsp70/Hsp90 organizing protein, and exerts antitumor activity in vitro and in vivo [J] . Wang Wenqian, Liu Yang, Zhao Zhixin, Cancer science. . 2016,第6期

机译：Y-632通过破坏HSP90和HSP70 / HSP90组织蛋白质之间的相互作用来抑制热休克蛋白90（HSP90）功能，并在体外和体内施加抗肿瘤活性
4. Investigation of the Hsp90 chaperone assembly, Hsp70 cycle and transfer of a client protein [C] . Nina Morgner, Ima Obong-Ebong, Carol V. Robinson American Society for Mass Spectrometry Conference on Mass Spectrometry and Allied Topics . 2012

机译：调查HSP90伴侣组件，HSP70循环和客户蛋白的转移
5. Combination immunotherapy targeting HSP90 DNA repair client proteins overexpressed in melanoma. [D] . Raveendran, Subhara. 2016

机译：靶向HSP90 DNA的组合免疫疗法修复在黑色素瘤中过表达的客户蛋白质。
6. Hsp 70/Hsp 90 organizing protein as a nitrosylation target in cystic fibrosis therapy [O] . Nadzeya V. Marozkina, Sean Yemen, Molly Borowitz, 2010

机译：Hsp 70 / Hsp 90组织蛋白在囊性纤维化治疗中作为亚硝化靶标
7. Hsp 70/Hsp 90 organizing protein as a nitrosylation target in cystic fibrosis therapy [O] . Marozkina, Nadzeya V., Yemen, Sean, Borowitz, Molly, 2010

机译：Hsp 70 / Hsp 90组织蛋白在囊性纤维化治疗中作为亚硝化靶标

Hsp 70/Hsp 90 organizing protein as a nitrosylation target in cystic fibrosis therapy

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