通过一种依赖于GRASP的非传统分泌途径来拯救 ΔF508-CFTR 的贩运
Heon Yung Gee1, Shin Hye Noh, Bor Luen Tang
1Department of Pharmacology, Brain Korea 21 Project for Medical Sciences, Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul 120-752, Korea.
Cell
|September 3, 2011
概括
囊性纤维化突变 ΔF508-CFTR 表面表达通过一种非传统的依赖 GRASP 的途径恢复. 这种方法在小鼠中拯救了CFTR功能和生存,提供了潜在的治疗策略.
科学领域:
- 分子生物学分子生物学
- 细胞生物学 细胞生物学
- 生理学 生理学 生理学
背景情况:
- 囊性纤维化的主要突变,Phe508删除 (ΔF508),损害了CFTR蛋白贩运和细胞表面表达.
- 传统的蛋白质分泌途径无法正确地将 ΔF508-CFTR 传输到细胞表面.
研究的目的:
- 为了研究一种非传统的分泌途径来拯救 ΔF508-CFTR 表面表达.
- 探索GRASP依赖分泌在纠正CFTR功能障碍中的作用.
主要方法:
- 利用分子和生理分析来研究CFTR贩运.
- 研究了ER引起压力的途径和GRASP介导的分泌.
- 检查了对贩运至关重要的酸化和蛋白质相互作用.
- 产生了表达GRASP的转基因 ΔF508-CFTR 小鼠.
主要成果:
- ΔF508-CFTR表面表达在体外和体内通过一种依赖GRASP的途径被拯救.
- 通过这种非常规的路线,ER压力机制促进了野生类型和 ΔF508-CFTR 的贩运.
- 酸化GRASP及其基于PDZ与CFTR的相互作用对于此次救援至关重要.
- 转基因GRASP在小鼠中的表达恢复了CFTR功能,并改善了无毒性生存率.
结论:
- 非传统的GRASP依赖分泌提供了一个可行的策略来纠正ΔF508-CFTR缺陷.
- 这条路径提供了对ER压力中介蛋白质贩运的见解.
- 向GRASP代表了囊性纤维化和其他蛋白质错折疾病的潜在治疗途径.
相关概念视频
01:45Vesicular Tubular Clusters
After budding out from the ER membrane, some COPII vesicles lose their coat and fuse with one another to form larger vesicles and interconnected tubules called vesicular tubular clusters or VTCs. These clusters constitute a compartment at the ER-Golgi interface known as ERGIC (Endoplasmic Reticulum Golgi Intermediate Compartment). The ERGIC is a mobile membrane-bound cargo transport system that sorts proteins secreted from ER and delivers them to the Golgi.
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01:45ER Retrieval Pathway
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01:20Cotranslational Protein Translocation
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Sec61 channel partners for cotranslational translocation
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Sec61 channel partners for cotranslational translocation
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01:27Post-translational Translocation of Proteins to the RER
A sizable fraction of proteins destined for ER are first synthesized in the cell cytosol and then transported across the ER membrane–a process called post-translational translocation. Similar to cotranslationally translocated proteins, these proteins also use the Sec translocon complex to enter the ER lumen.
Targeting proteins to the ER
Hsp40 and Hsp70 chaperone molecules bind the translated proteins in the cytosol to prevent their folding. The chaperone binding helps to keep the signal...
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01:32Export of Misfolded Proteins out of the ER
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01:12Clathrin Coated Vesicles
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