Hsp 70/Hsp 90 organizing protein as a nitrosylation target in cystic fibrosis therapy.
The endogenous signaling molecule S-nitrosoglutathione (GSNO) and other S-nitrosylating agents can cause full maturation of the abnormal gene product DeltaF508 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 DeltaF508 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 DeltaF508 CFTR. Hop knockdown using siRNA recapitulated the effect of GSNO on DeltaF508 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 DeltaF508 CFTR trafficking by inhibiting Hop expression, and that combination therapies--using differing mechanisms of action--may have additive benefits in treating CF.
Marozkina
Nadzeya V
NV
Department of Pediatric Respiratory Medicine, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.
Yemen
Sean
S
Borowitz
Molly
M
Liu
Lei
L
Plapp
Melissa
M
Sun
Fei
F
Islam
Rafique
R
Erdmann-Gilmore
Petra
P
Townsend
R Reid
RR
Lichti
Cheryl F
CF
Mantri
Sneha
S
Clapp
Phillip W
PW
Randell
Scott H
SH
Gaston
Benjamin
B
Zaman
Khalequz
K
D002352:Carrier Proteins / Q000235:genetics* / Q000502:physiology*; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D003550:Cystic Fibrosis / Q000235:genetics / Q000628:therapy*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics; D004721:Endoplasmic Reticulum / Q000378:metabolism; D015316:Genetic Therapy / Q000379:methods; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism*; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D008954:Models, Biological; D009154:Mutation; D009584:Nitrogen / Q000737:chemistry*; D026422:S-Nitrosoglutathione / Q000737:chemistry; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000502:physiology*; D018832:Molecular Chaperones
D002352:Carrier Proteins; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D018840:HSP70 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; D009584:Nitrogen; D026422:S-Nitrosoglutathione; D025521:Tumor Suppressor Proteins; C505032:CFTR protein, human; C101119:ST13 protein, human; D018832:Molecular Chaperones