Abstract
The CFTR (cystic fibrosis transmembrane conductance regulator) protein is a large polytopic protein whose biogenesis is inefficient. To better understand the regulation of CFTR processing and trafficking, we conducted a genetic screen that identified COMMD1 as a new CFTR partner. COMMD1 is a protein associated with multiple cellular pathways, including the regulation of hepatic copper excretion, sodium uptake through interaction with ENaC (epithelial sodium channel) and NF-kappaB signaling. In this study, we show that COMMD1 interacts with CFTR in cells expressing both proteins endogenously. This interaction promotes CFTR cell surface expression as assessed by biotinylation experiments in heterologously expressing cells through regulation of CFTR ubiquitination. In summary, our data demonstrate that CFTR is protected from ubiquitination by COMMD1, which sustains CFTR expression at the plasma membrane. Thus, increasing COMMD1 expression may provide an approach to simultaneously inhibit ENaC absorption and enhance CFTR trafficking, two major issues in cystic fibrosis.
Highlights
The cystic fibrosis transmembrane conductance regulator (CFTR) is a cAMP-regulated Cl- channel encoded by the gene mutated in cystic fibrosis (CF) [1]
CFTR interact in epithelial cells A yeast two-hybrid screen was performed to identify proteins that interact with CFTR amino acids Leu937 to Pro988 (Figure 1A) [15]
Co-immunoprecipitation experiments performed on HT-29 cells showed an association between COMMD1 and wild-type CFTR (wt-CFTR) in vivo when using anti-CFTR antibody (Figure 1B)
Summary
The cystic fibrosis transmembrane conductance regulator (CFTR) is a cAMP-regulated Cl- channel encoded by the gene mutated in cystic fibrosis (CF) [1]. The lack of CFTR function at the apical membrane of epithelial cells is the cause of the morbidity and mortality associated with the disease [2]. CFTR is a large polytopic protein whose biogenesis is inefficient and slow, with 60–80% of CFTR being degraded in the endoplasmic reticulum (ER) [3,4]. It is the first integral membrane protein shown to be a substrate for ER-associated degradation (ERAD) via the ubiquitin proteasome system. Ubiquitination can regulate CFTR at the plasma membrane and internalized CFTR can either be ubiquitinated and diverted for lysosomal degradation or can be recycled back to the cell surface [7,8,9,10]. Identifying new regulators of CFTR membrane trafficking in post-Golgi compartments is still a major research issue
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