The multiple ubiquitination mechanisms in CFTR peripheral quality control

The cystic fibrosis transmembrane conductance regulator (CFTR) is a cAMP-regulated anion channel, which is expressed on the apical plasma membrane (PM) of epithelial cells. Mutations in the CFTR gene cause cystic fibrosis (CF), one of the most common genetic diseases among Caucasians. Most CF-associated mutations result in misfolded CFTR proteins that are degraded by the endoplasmic reticulum quality control (ERQC) mechanism. However, the mutant CFTR reaching the PM through therapeutic agents is still ubiquitinated and degraded by the peripheral protein quality control (PeriQC) mechanism, resulting in reduced therapeutic efficacy. Moreover, certain CFTR mutants that can reach the PM under physiological conditions are degraded by PeriQC. Thus, it may be beneficial to counteract the selective ubiquitination in PeriQC to enhance therapeutic outcomes for CF. Recently, the molecular mechanisms of CFTR PeriQC have been revealed, and several ubiquitination mechanisms, including both chaperone-dependent and-independent pathways, have been identified. In this review, we will discuss the latest findings related to CFTR PeriQC and propose potential novel therapeutic strategies for CF.

Automated summary

The CFTR protein is responsible for transporting ions and is regulated by cAMP. Mutations in the CFTR gene result in the genetic disease cystic fibrosis. While most CF-associated mutations lead to the degradation of mutant CFTR proteins, therapeutic agents that allow mutant CFTR to reach the cell membrane are still subject to degradation, reducing their effectiveness. This review discusses the latest understanding of the mechanisms of CFTR degradation and proposes potential new therapeutic strategies for cystic fibrosis.