commd1-mediated ubiquitination regulates cftr traffickingcommd1-mediated泛素化调节雌性生殖道贩卖.pdfVIP

COMMD1-Mediated Ubiquitination Regulates CFTR Trafficking ¨ ´ 1,2 ¨ 1,2 1 1 ` 1,2,3 Loıc Drevillon , Gaelle Tanguy , Alexandre Hinzpeter , Nicole Arous , Alix de Becdelievre , Abdel Aissat1,2, Agathe Tarze1,2, Michel Goossens1,2,3, Pascale Fanen1,2,3* ´ ´ ´ ´ ´ ´ 1 INSERM, Unite U955, Creteil, France, 2 Universite Paris-Est, Faculte de Medecine, UMR-S 955, Creteil, France, 3 AP-HP, Groupe Henri-Mondor Albert-Chenevier, Service de ´ ´ ´ Biochimie-Genetique, Creteil, France 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