Functional Consequences of CFTR Interactions in Cystic Fibrosis.

Abstract

Cystic fibrosis (CF) is a fatal autosomal recessive disorder caused by the loss of function mutations within a single gene for the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR). CFTR is a chloride channel that regulates ion and fluid transport across various epithelia. The discovery of CFTR as the CF gene and its cloning in 1989, coupled with extensive research that went into the understanding of the underlying biological mechanisms of CF, have led to the development of revolutionary therapies in CF that we see today. The highly effective modulator therapies have increased the survival rates of CF patients and shifted the epidemiological landscape and disease prognosis. However, the differential effect of modulators among CF patients and the presence of non-responders and ineligible patients underscore the need to develop specialized and customized therapies for a significant number of patients. Recent advances in the understanding of the CFTR structure, its expression, and defined cellular compositions will aid in developing more precise therapies. As the lifespan of CF patients continues to increase, it is becoming critical to clinically address the extra-pulmonary manifestations of CF disease to improve the quality of life of the patients. In-depth analysis of the molecular signature of different CF organs at the transcriptional and post-transcriptional levels is rapidly advancing and will help address the etiological causes and variability of CF among patients and develop precision medicine in CF. In this review, we will provide an overview of CF disease, leading to the discovery and characterization of CFTR and the development of CFTR modulators. The later sections of the review will delve into the key findings derived from single-molecule and single-cell-level analyses of CFTR, followed by an exploration of disease-relevant protein complexes of CFTR that may ultimately define the etiological course of CF disease.