A molecular switch in the scaffold NHERF1 enables misfolded CFTR to evade the peripheral quality control checkpoint

• DOI: 10.1126/scisignal.aaa1580
• Publication Date: 2015-05-19T18:35:14Z
• Authors: Cláudia A. Loureiro; Ana Margarida Matos; Ângela Dias-Alves; Joana F. Pereira; Inna Uliyakina; Patrícia Barros; Margarida D. Amaral; Paulo Matos
• Keywords: PDZ domain; Moesin

The peripheral protein quality control (PPQC) checkpoint removes improperly folded proteins from the plasma membrane through a mechanism involving E3 ubiquitin ligase CHIP (carboxyl terminus of Hsc70 interacting protein). PPQC limits efficacy some cystic fibrosis (CF) drugs, such as VX-809, that improve trafficking to misfolded mutants CF transmembrane conductance regulator (CFTR), including F508del-CFTR, which retains partial functionality. We investigated in lung epithelial cells with F508del-CFTR were exposed VX-809. conformation scaffold NHERF1 (Na(+)/H(+) exchange regulatory factor 1) determined whether recognized "rescued" (the portion reached cell surface VX-809-treated cells). Activation cytoskeletal Rac1 promoted an interaction between actin-binding adaptor ezrin and NHERF1, triggering exposure second PDZ domain interacted rescued F508del-CFTR. Because binding precluded recruitment CHIP, coexposure airway activator nearly tripled Interference NHERF1-ezrin prevented increase VX-809 by activation, but was not required for efficacy. Thus, rather than mainly directing anchoring actin cytoskeleton, induction activation signaling triggered conformational change then able bind stabilize CFTR at membrane. These insights into stabilization provide new targets treatment CF.