From the endoplasmic reticulum to the plasma membrane: mechanisms of CFTR folding and trafficking

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• 作者：Carlos M. Farinha ; Sara Canato
• 关键词：CFTR ; Cystic fibrosis ; Endoplasmic reticulum quality control ; Folding ; Trafficking ; Membrane stability
• 刊名：Cellular and Molecular Life Sciences
• 出版年：2017
• 出版时间：January 2017
• 年：2017
• 卷：74
• 期：1
• 页码：39-55
• 全文大小：
• 刊物类别：Biomedical and Life Sciences
• 刊物主题：Cell Biology; Biomedicine, general; Life Sciences, general; Biochemistry, general;
• 出版者：Springer International Publishing
• ISSN：1420-9071
• 卷排序：74

文摘

CFTR biogenesis starts with its co-translational insertion into the membrane of endoplasmic reticulum and folding of the cytosolic domains, towards the acquisition of a fully folded compact native structure. Efficiency of this process is assessed by the ER quality control system that allows the exit of folded proteins but targets unfolded/misfolded CFTR to degradation. If allowed to leave the ER, CFTR is modified at the Golgi and reaches the post-Golgi compartments to be delivered to the plasma membrane where it functions as a cAMP- and phosphorylation-regulated chloride/bicarbonate channel. CFTR residence at the membrane is a balance of membrane delivery, endocytosis, and recycling. Several adaptors, motor, and scaffold proteins contribute to the regulation of CFTR stability and are involved in continuously assessing its structure through peripheral quality control systems. Regulation of CFTR biogenesis and traffic (and its dysregulation by mutations, such as the most common F508del) determine its overall activity and thus contribute to the fine modulation of chloride secretion and hydration of epithelial surfaces. This review covers old and recent knowledge on CFTR folding and trafficking from its synthesis to the regulation of its stability at the plasma membrane and highlights how several of these steps can be modulated to promote the rescue of mutant CFTR.