Genetic Inhibition Of The Ubiquitin Ligase Rnf5 Attenuates Phenotypes Associated To F508del Cystic Fibrosis Mutation

被引：43

作者：

Tomati, Valeria ^{[1
]}

Sondo, Elvira ^{[1
]}

Armirotti, Andrea ^{[2
]}

Caci, Emanuela ^{[1
]}

Pesce, Emanuela ^{[1
]}

Marini, Monica ^{[1
]}

Gianotti, Ambra ^{[1
]}

Jeon, Young Ju ^{[3
]}

Cilli, Michele ^{[4
]}

Pistorio, Angela ^{[1
]}

Mastracci, Luca ^{[4
,5
]}

Ravazzolo, Roberto ^{[1
,6
]}

Scholte, Bob ^{[7
]}

Ronai, Ze'ev ^{[3
]}

Galietta, Luis J. V. ^{[1
]}

Pedemonte, Nicoletta ^{[1
]}

机构：

[1] Ist Giannina Gaslini, I-16148 Genoa, Italy

[2] Ist Italiano Tecnol, Dept Drug Discovery & Dev, Genoa, Italy

[3] Burnham Inst Med Res, La Jolla, CA USA

[4] IRCCS AOU San Martino IST, Genoa, Italy

[5] Univ Genoa, Anat Pathol Unit, Dept Surg Sci & Integrated Diagnost, Genoa, Italy

[6] Univ Genoa, DINOGMI Dept, Genoa, Italy

[7] Erasmus MC, Cell Biol Dept, Rotterdam, Netherlands

来源：

SCIENTIFIC REPORTS | 2015年 / 5卷

关键词：

TRANSMEMBRANE-CONDUCTANCE-REGULATOR; RETICULUM-ASSOCIATED DEGRADATION; CFTR CHLORIDE CHANNEL; ENDOPLASMIC-RETICULUM; PROTEIN; DELTA-F508-CFTR; EXPRESSION; RESCUE; DOMAIN; SECRETION;

D O I：

10.1038/srep12138

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Cystic fibrosis (CF) is caused by mutations in the CFTR chloride channel. Deletion of phenylalanine 508 (F508del), the most frequent CF mutation, impairs CFTR trafficking and gating. F508del-CFTR mistrafficking may be corrected by acting directly on mutant CFTR itself or by modulating expression/activity of CFTR-interacting proteins, that may thus represent potential drug targets. To evaluate possible candidates for F508del-CFTR rescue, we screened a siRNA library targeting known CFTR interactors. Our analysis identified RNF5 as a protein whose inhibition promoted significant F508del-CFTR rescue and displayed an additive effect with the investigational drug VX-809. Significantly, RNF5 loss in F508del-CFTR transgenic animals ameliorated intestinal malabsorption and concomitantly led to an increase in CFTR activity in intestinal epithelial cells. In addition, we found that RNF5 is differentially expressed in human bronchial epithelia from CF vs. control patients. Our results identify RNF5 as a target for therapeutic modalities to antagonize mutant CFTR proteins.

引用

页数：17

共 62 条

[1] Small heat shock proteins target mutant cystic fibrosis transmembrane conductance regulator for degradation via a small ubiquitin-like modifier-dependent pathway [J].