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.

调节内质网（ER）中膜蛋白成熟和分泌途径的多步过程在许多蛋白错误折叠疾病中均受到破坏。离子通道CFTR中的突变会削弱其折叠并随后定位于质膜，从而导致囊性纤维化（CF），这是一种遗传性疾病，最终致命，它损害了多个器官（主要是肺）的功能。在这里，我们发现CFTR的正确成熟取决于蛋白质调节插入（RI）元件中的磷酸化和甲基化事件之间的串扰。操纵这些翻译后修饰（PTM）可以防止野生型CFTR的成熟，而是通过ER质量控制系统诱导其降解。删除Phe ⁵⁰⁸（ΔF508）是CF中最普遍的突变，以及CFTR中影响其运输的其他突变，例如N1303K，也导致了定量和定性的PTM变化，从而阻止了错折叠的CFTR的成熟。进一步的分析显示，当细胞在28°C下但仅在激酶CK2α存在时，野生型CFTR样PTM模式和功能在ΔF508CFTR中得以恢复。此外，复制此PTM模式的能力预示了治疗恢复ΔF508CFTR活性的功效。因此，对患者信息的评估表明，几个修饰位点的点突变与临床CF相关。这些发现确定了CFTR成熟的最小定量和定性PTM代码，可正确区分折叠的CFTR和错误折叠的CFTR。