COMMD1-Mediated Ubiquitination Regulates CFTR Trafficking

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.

Clusterin and COMMD1 Independently Regulate Degradation of the Mammalian Copper ATPases ATP7A and ATP7B

“…The action of COMMD1 in facilitating the degradation of ATP7B via the proteasomal pathway is consistent with this. However, contrary to these studies, COMMD1 interaction with the cystic fibrosis transmembrane conductance regulator (CFTR) protein enhanced CFTR stability and cell surface expression (69). COMMD1 also was shown to exist in a complex with CCS and SOD1 and inhibits the formation of SOD1 dimers, which is the final step in SOD1 activation (62).…”

Regulation of Activation and Processing of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) by a Complex Electrostatic Interaction between the Regulatory Domain and Cytoplasmic Loop 3

“…What is more, CL3 also involves ubiquitinationdependent CFTR trafficking (32). Finally, D979A in CF patients causes misprocessing (33).…”

Interference with Ubiquitination in CFTR Modifies Stability of Core Glycosylated and Cell Surface Pools

“…Previous research shows that ubiquitination is one of the key steps in determining the CFTR destination during trafficking (8,35). Our eight mutants do not show any differences in the ability to complex with these cargo proteins (Fig.…”