Stress activated MAPK influence the quality control of misfolded cystic fibrosis transmembrane conductance regulator.

Abstract

Cystic fibrosis transmembrane conductance regulator (CFTR) deletion mutation of phenylalanine at position 508 (DF508CFTR) causes 70% Cystic Fibrosis (CF) disease that affects 1 in 2000 live births among Caucasians. This mutation results in misfolding and subsequent retention of the protein in the endoplasmic reticulum (ER) and later removal by ER associated degradation (ERAD). Proteins that are folded in the ER have to pass an obligatory quality control (ERQC) before they can be transported out of the ER to other downstream compartments of the secretory pathway. Here we have used a systems biology based analysis of the mode of action of drugs that have been published to allow the DF508CFTR to cross the ERQC, to arrive at molecular pathways that modulate the ERQC. Our findings here point to a role of stress activated MAPK (SAPK) pathway in the increasing the ERQC threshold that contributes to the ER retention of the already misfolded mutant CFTR. Downregulation of the MAPK by siRNA or inhibition of this pathway using drugs can allow the DF508CFTR to escape the ERQC and reach the plasma membrane.