Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 107, Issue 25, Pages 11393-11398Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0909128107
Keywords
cystic fibrosis transmembrane conductance regulator; S-nitrosoglutathione corrector; treatment
Categories
Funding
- Cystic Fibrosis Foundation Research [Zaman 04GO, R026-CR07]
- National Institutes of Health (NIH) [3 RO1 HL 59337]
- NIH National Center for Research Resources [P41RR000954, UL1 RR024992]
- W. M. Keck Foundation
- Ivy Foundation
Ask authors/readers for more resources
The endogenous signaling molecule S-nitrosoglutathione (GSNO) and other S-nitrosylating agents can cause full maturation of the abnormal gene product Delta F508 cystic fibrosis (CF) transmembrane conductance regulator (CFTR). However, the molecular mechanism of action is not known. Here we show that Hsp70/Hsp90 organizing protein (Hop) is a critical target of GSNO, and its S-nitrosylation results in Delta F508 CFTR maturation and cell surface expression. S-nitrosylation by GSNO inhibited the association of Hop with CFTR in the endoplasmic reticulum. This effect was necessary and sufficient to mediate GSNO-induced cell-surface expression of Delta F508 CFTR. Hop knockdown using siRNA recapitulated the effect of GSNO on Delta F508 CFTR maturation and expression. Moreover, GSNO acted additively with decreased temperature, which promoted mutant CFTR maturation through a Hop-independent mechanism. We conclude that GSNO corrects Delta F508 CFTR trafficking by inhibiting Hop expression, and that combination therapies-using differing mechanisms of action-may have additive benefits in treating CF.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available