The RNA Binding Protein Tristetraprolin Contributes to CFTR mRNA Stability in Cystic Fibrosis.

Abstract

Cystic Fibrosis (CF) is the most common inherited disorder and is characterized by an inflammatory phenotype. Here, we found that in bronchial epithelium reconstituted form lung tissue biopsies from patients with CF, the RNA-binding protein tristetraprolin (TTP), a key regulator of inflammation, is dysregulated in cells that strongly express cytokines and interleukins. TTP activity is regulated by extensive post-translational modifications, particularly phosphorylation. We found that in addition to mRNA downregulation, phosphorylated TTP (which cannot bind to mRNA) accumulated in CF cultures, suggesting that the imbalance in TTP phosphorylation status could contribute to the inflammatory phenotype in CF. We confirmed TTP destabilizing role on IL8 mRNA through its 3'UTR sequence in CF cells. We next demonstrated that TTP phosphorylation is mainly regulated by MK2 through activation of ERK, which also was hyperphosphorylated. TTP is considered a mRNA decay factor with some exception, and we present a new positive role of TTP in CF cultures. We determined that TTP binds to specific ARE motifs on the 3'UTR of mRNA sequences and also, for the first time, to the 3'UTR of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) where TTP binding stabilizes the mRNA level. This study identified new partners that can be targeted in CF and proposes a new way to control CFTR gene expression.