Research ArticleBiochemistry

A posttranslational modification code for CFTR maturation is altered in cystic fibrosis

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Science Signaling  01 Jan 2019:
Vol. 12, Issue 562, eaan7984
DOI: 10.1126/scisignal.aan7984

Breaking the code to cystic fibrosis

Cystic fibrosis is an inherited disease that severely impairs the function of lungs and other organs. Treatments only manage the symptoms and eventually are insufficient. Understanding more about the mutations in the chloride channel protein CFTR that cause the disease may lead to improved and targeted therapies. Pankow et al. examined the posttranslational modifications on wild-type and mutant CFTR in bronchial epithelial cells and found that mutation-induced misfolding prevented phosphorylation of CFTR by the kinase CK2α and subsequent methylation elsewhere. Instead, those sites were ubiquitylated, marking the protein for degradation. These findings reveal insight into the mechanisms promoting CFTR maturation, trafficking, and function that are lost by the mutations that cause cystic fibrosis.


The multistep process regulating the maturation of membrane proteins in the endoplasmic reticulum (ER) and the secretory pathway is disrupted in many protein misfolding disorders. Mutations in the ion channel CFTR that impair its folding and subsequent localization to the plasma membrane cause cystic fibrosis (CF), an inherited and eventually lethal disease that impairs the function of multiple organs, mostly the lungs. Here, we found that proper maturation of CFTR is dependent on cross-talk between phosphorylation and methylation events in the regulatory insertion (RI) element of the protein. Manipulating these posttranslational modifications (PTMs) prevented the maturation of wild-type CFTR and instead induced its degradation by ER quality control systems. Deletion of Phe508 (ΔF508), the most prevalent mutation in CF, and other mutations in CFTR that impair its trafficking, such as N1303K, also led to quantitative and qualitative PTM changes that prevented the maturation of misfolded CFTR. Further analysis revealed that a wild-type CFTR–like PTM pattern and function was restored in ΔF508 CFTR when cells were cultured at 28°C but only in the presence of the kinase CK2α. Furthermore, the ability to replicate this PTM pattern predicted the efficacy of treatments in restoring ΔF508 CFTR activity. Accordingly, evaluation of patient information revealed that point mutations of several of the modification sites are associated with clinical CF. These findings identify a minimal quantitative and qualitative PTM code for CFTR maturation that distinguishes correctly folded from misfolded CFTR.

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