High-throughput screening identifies FAU protein as a regulator of mutant cystic fibrosis transmembrane conductance regulator channel

Valeria Tomati, Emanuela Pesce, Emanuela Caci, Elvira Sondo, Paolo Scudieri, Monica Marini, Felice Amato, Giuseppe Castaldo, Roberto Ravazzolo, Luis J.V. Galietta, Nicoletta Pedemonte

Research output: Contribution to journalArticlepeer-review


In cystic fibrosis, deletion of phenylalanine 508 (F508del) in the cystic fibrosis transmembrane conductance regulator (CFTR) anion channel causes misfolding and premature degradation. One possible approach to reducing the detrimental health effects of cystic fibrosis could be the identification of proteins whose suppression rescues F508del-CFTR function in bronchial epithelial cells. However, searches for these potential targets have not yet been conducted, particularly in a relevant airway background using a functional readout. To identify proteins associated with F508del-CFTR processing, we used a highthroughput functional assay to screen an siRNA library targeting 6,650 different cellular proteins. We identified 37 proteins whose silencing significantly rescued F508del-CFTR activity, as indicated by enhanced anion transport through the plasma membrane. These proteins included FAU, UBE2I, UBA52, MLLT6, UBA2, CHD4, PLXNA1, and TRIM24, among others. We focused our attention on FAU, a poorly characterized protein with unknown function. FAU knockdown increased the plasma membrane targeting and function of F508del-CFTR, but not of wildtype CFTR. Investigation into the mechanism of action revealed a preferential physical interaction of FAU with mutant CFTR, leading to its degradation. FAU and other proteins identified in our screening may offer a therapeutically relevant panel of drug targets to correct basic defects in F508del-CFTR processing.

Original languageEnglish
Pages (from-to)1203-1217
Number of pages15
JournalJournal of Biological Chemistry
Issue number4
Publication statusPublished - Jan 1 2018

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology


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