Cutting edge Seminar

 

Speaker: Tsukasa Okiyoneda  (Professor,  School of Science and Technology, Graduate School of Science, Kwansei Gakuin University)

Title: CFTR protein quality control and its application to CF drug discovery

 

Date&Time: 29 Jan.  (Wed.) 2020, 12:00- 13:00

Venue: Conference Room(1F), IMEG

 

Abstract:

Cystic fibrosis (CF), one of the most common inherited disease in the Caucasian population, is caused by mutations of the CF transmembrane conductance regulator (CFTR), a cAMP-regulated chloride channel localized at the apical plasma membrane (PM) of epithelia. Deletion of F508 (ΔF508), the most common CF mutation (~90%), causes global misfolding of the CFTR, resulting in marginal PM expression of the partially functional channel. Most of the misfolded CFTR is recognized by the endoplasmic reticulum (ER) and cytosolic quality control (QC) mechanisms and degraded by ubiquitin (Ub)-proteasome system, a process known as ER-associated degradation (ERAD). A small fraction of the misfolded CFTR could be detected at the PM, and this PM expression can be augmented by CF drugs such as CFTR correctors (e.g., VX-809). However, ΔF508 CFTR is rapidly eliminated from PM by peripheral QC mechanism, hampering the therapeutic efforts (Okiyoneda et al, Science 2010, Okiyoneda, Nat Chem Biol 2013).

Our comprehensive siRNA screen has discovered Ub ligases responsible for the ER and peripheral protein QC of CFTR (Okiyoneda et al, Dev Cell 2018). Counteracting the activity of these Ub ligases stabilizes ΔF508 CFTR at the ER and PM by attenuating the ubiquitination, and improves the limited therapeutic effort of CF drug in cell culture models. Thus, the development of the CFTR Ub ligase inhibitors could help overcome the limited efficacy of CF pharmacological therapy (Fukuda & Okiyoneda, Front Pharmacol. 2018).