Oxidant stress suppresses CFTR expression

Cantin, André M.; Bilodeau, Ginette; Ouellet, Cristine; Liao, Jie; Hanrahan, John W.

doi:10.1152/ajpcell.00070.2005

Cited by 92 publications

(83 citation statements)

References 60 publications

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“…Although further investigations may be needed to clarify this hypothesis, it is likely that under a stress condition in which CRT is up-regulated (25,26), CRT may be expressed at the cell surface and interact with CFTR, which may stimulate the endocytosis of CFTR and direct it to proteasomal degradation. Recently (during the preparation of this manuscript), it was reported that oxidant stress suppresses CFTR expression (44). Therefore, CRT may enhance the degradation of CFTR by oxidant stress.…”

Section: Discussionmentioning

confidence: 93%

Calreticulin Negatively Regulates the Cell Surface Expression of Cystic Fibrosis Transmembrane Conductance Regulator

Harada

Okiyoneda

Hashimoto

et al. 2006

Journal of Biological Chemistry

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Cystic fibrosis transmembrane conductance regulator (CFTR) is a cAMP-dependent Cl؊ channel at the plasma membrane, and its malfunction results in cystic fibrosis, the most common lethal genetic disease in Caucasians. Quality control of CFTR is strictly regulated by several molecular chaperones. Here we show that calreticulin (CRT), which is a lectin-like chaperone in the endoplasmic reticulum (ER), negatively regulates the cell surface CFTR. RNA interference-based CRT knockdown induced the increase of CFTR expression. Consistently, this effect was observed in vivo. CRT heterozygous (CRT ؉/؊ ) mice had a higher endogenous expression of CFTR than the wild-type mice. Moreover, CRT overexpression induced cell surface expression of CRT, and it significantly decreased the cell surface expression and function of CFTR. CRT overexpression destabilized the cell surface CFTR by enhancing endocytosis, leading to proteasomal degradation. Deletion of the carboxyl domain of CRT, which results in its ER export, increased the negative effect and enhanced the interaction with CFTR. Thus, CRT in the post-ER compartments may act as a negative regulator of the cell surface CFTR.Cystic fibrosis transmembrane conductance regulator (CFTR) 3 is a polytopic integral membrane protein, which functions as a cAMP-dependent Cl Ϫ channel at the plasma membrane (1-4). Mutations in the CFTR gene lead to the absence or malfunction of a regulated Cl Ϫ channel in the apical membrane of secretory epithelia resulting in the clinical symptoms of cystic fibrosis, which is the most common lethal genetic disease in Caucasians (5). After translation, CFTR is folded in the endoplasmic reticulum (ER) assisted by several chaperone proteins, but only ϳ30% of the immature CFTR is exported from the ER to the Golgi and converted to the mature form by oligosaccharide processing (6). Ultimately, mature CFTR reaches the plasma membrane where it functions as a regulated Cl Ϫ channel (6). However, ϳ70% of immature CFTR is retained in the ER by the ER quality control system (6, 7). The ERretained immature CFTR is ultimately ubiquitinated by an ubiquitin ligase, CHIP (carboxyl terminus of HSC70-interacting protein), and degraded by proteasomes, which is known as ER-associated degradation (ERAD) (8 -11). In contrast, all ⌬F508 CFTR (ϳ 99%), the most common mutant of CFTR in cystic fibrosis patients, is retained in the ER, leading to ERAD (6, 7). Several chaperone proteins are involved in the quality control of CFTR. During insertion into the ER membrane, cytosolic chaperones Hsp70/Hsc70, Hdj-2, and Hsp90 interact with immature CFTR to stimulate productive folding (12-14). Moreover, cytosolic HspBP1 attenuates the activity of CHIP ubiquitin ligase, resulting in the inhibition of ERAD and stimulation of CFTR maturation (15). An ER-resident lectinlike chaperone, calnexin (CNX), also participates in the quality control of CFTR (7, 16). CNX interacts with immature CFTR via monoglucosylated oligosaccharide to attenuate the ERAD, resulting in the stimulation of CFTR folding (7...

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Section: Discussionmentioning

confidence: 93%

Calreticulin Negatively Regulates the Cell Surface Expression of Cystic Fibrosis Transmembrane Conductance Regulator

Harada

Okiyoneda

Hashimoto

et al. 2006

Journal of Biological Chemistry

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“…The reducing environment found in healthy lung cells prevents generation of an exaggerated inflammatory response to inhaled stresses. An oxidative environment, however, influences multiple intracellular signaling events, leading to apoptosis, increased synthesis and secretion of mucin [21], and alterations in ion transport including chloride secretion [22][23][24][25][26]. The result is a cascade of excessive inflammation, mediator release, and tissue injury-events that characterize CF lung disease.…”

Section: Oxidative Stress In the Lungmentioning

confidence: 99%

“…The great majority of this is in the reduced state: 96% of the GSH in ELF of nonsmokers and 98% of that in smokers are reduced. In human epithelial cells, the GSH increase induced by oxidants and cigarette smoke is associated with a simultaneous decrease in CFTR function [26,52]. CFTR function is also decreased in healthy smokers as determined by nasal potential difference measurements [52], a response that may represent an antioxidant defense aimed at transiently increasing mucus viscosity and decreasing GSH loss from epithelial cells.…”

Section: Antioxidants In the Airway Lumen Mucinmentioning

confidence: 99%

Antioxidants in cystic fibrosis☆Conclusions from the CF Antioxidant Workshop, Bethesda, Maryland, November 11-12, 2003

Cantin

White

Cross

et al. 2007

Free Radical Biology and Medicine

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Although great strides are being made in the care of individuals with cystic fibrosis (CF), this condition remains the most common fatal hereditary disease in North America. Numerous links exist between progression of CF lung disease and oxidative stress. The defect in CF is the loss of function of the transmembrane conductance regulator (CFTR) protein; recent evidence that CFTR expression and function are modulated by oxidative stress suggests that the loss may result in a poor adaptive response to oxidants. Pancreatic insufficiency in CF also increases susceptibility to deficiencies in lipophilic antioxidants. Finally the airway infection and inflammatory processes in the CF lung are potential sources of oxidants that can affect normal airway physiology and contribute to the mechanisms causing characteristic changes associated with bronchiectasis and loss of lung function. These multiple abnormalities in the oxidant/antioxidant balance raise several possibilities for therapeutic interventions that must be carefully assessed. IntroductionCystic fibrosis (CF) is the most common fatal disease caused by a single gene defect in Europe and North America [1,2]. The defective gene was identified in 1989 [3][4][5] and shown to encode the cystic fibrosis trans-membrane conductance regulator protein (CFTR). CFTR is a cyclic AMP-regulated anion channel with greatest selectivity for chloride, and bicarbonate [6][7][8]. Furthermore, CFTR regulates sodium transport across epithelial membranes through interactions with the epithelial sodium channel ENaC [9], and facilitates the trans-membrane export of the small organic anionic peptide glutathione [10]. The expression of CFTR is located in the apical membrane of epithelial cells that line mucous membranes and submucosal glands ☆ A list of participants may be found in the Acknowledgments.

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“…La protéine CFTR (cystic fibrosis transmembrane conductance regulator) est le seul membre de la famille des protéines ABC à être doté de la fonction d'un canal ionique perméable aux anions plutôt que de celle d'un transporteur actif [3]. Nos travaux récents suggèrent que la protéine CFTR pourrait, tout comme d'autres protéines ABC, jouer un rôle protecteur contre les radicaux libres car elle est fortement modulée par le stress oxydatif [4]. Le canal CFTR permet le déplacement transmembranaire des anions chlorures, du bicarbonate, et vraisemblablement du glutathion, à la surface apicale des cellules épithéliales [5].…”

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“…Ces mucines offrent une importante barrière protectrice pouvant interagir avec les oxydants [7]. de sodium ; de plus la stimulation du canal CFTR avec de l'isoprotérénol n'induit aucun changement de potentiel trans-épithélial nasal [10]. Chez des sujets sains nonfumeurs, la différence de potentiel est plus faible au repos, mais elle augmente à la suite d'une stimulation à l'isoprotérénol.…”

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