Correctors of the basic trafficking defect of the mutant F508del-CFTR that causes cystic fibrosis

Birault, Véronique; Solari, Roberto; Hanrahan, John W.; Thomas, David Y.

doi:10.1016/j.cbpa.2013.04.020

Cited by 31 publications

(39 citation statements)

References 40 publications

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“…Therefore, polyubiquitination, but not monoubiquitination, becomes virtually impossible if all of the lysine residues within ubiquitin are replaced by arginine (known as the lysine-less ubiquitin mutant, Ub-K0). For a given protein, if polyubiquitin chain formation is required for its degradation, then overexpressing the Ub-K0 mutant may effectively enhance its steady-state protein expression (Bloom et al, 2003;Volk et al, 2005). Figure 5A shows that Ub-K0 overexpression prominently upregulates Ca V 2.1 protein level by ϳ74%; in contrast, coexpression with ubiquitin WT (Ub-WT) significantly reduces Ca V 2.1 protein level by ϳ23%.…”

Section: Interaction and Colocalization Of Rnf138 With Ca V 21 In Nementioning

confidence: 99%

“…In both cases, the lack of complete functional recovery may be attributed to the foregoing membrane-trafficking deficit of Ca V 2.1 WT induced by EA2 mutants because functional expression is determined by both total protein level and membrane trafficking efficiency. The disease-causing CFTR ⌬F508 mutant is associated with severely impaired membrane trafficking that results in a virtual loss of functional expression and application of low temperature or chemical compounds is known to correct the CFTR mutant's membrane-trafficking defect successfully, thereby restoring its Cl-transport function; in fact, several chemical compounds are being carefully evaluated for their clinical potentials as pharmacological chaperones (Birault et al, 2013;Pranke and SermetGaudelus, 2014). Therefore, it will be essential in the future to search for novel chemical chaperones capable of correcting membrane trafficking of Ca V 2.1.…”

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confidence: 99%

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Ubiquitin Ligase RNF138 Promotes Episodic Ataxia Type 2-Associated Aberrant Degradation of Human Ca_v2.1 (P/Q-Type) Calcium Channels

Fu¹,

Jeng

Ma³

et al. 2017

J. Neurosci.

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Voltage-gated CaV2.1 channels comprise a pore-forming α1Asubunit with auxiliary α2δ and β subunits. CaV2.1 channels play an essential role in regulating synaptic signaling. Mutations in the human gene encoding the CaV2.1 subunit are associated with the cerebellar disease episodic ataxia type 2 (EA2). Several EA2-causing mutants exhibit impaired protein stability and exert dominant-negative suppression of CaV2.1 wild-type (WT) protein expression via aberrant proteasomal degradation. Here, we set out to delineate the protein degradation mechanism of human CaV2.1 subunit by identifying RNF138, an E3 ubiquitin ligase, as a novel CaV2.1-binding partner. In neurons, RNF138 and CaV2.1 coexist in the same protein complex and display notable subcellular colocalization at presynaptic and postsynaptic regions. Overexpression of RNF138 promotes polyubiquitination and accelerates protein turnover of CaV2.1. Disrupting endogenous RNF138 function with a mutant (RNF138-H36E) or shRNA infection significantly upregulates the CaV2.1 protein level and enhances CaV2.1 protein stability. Disrupting endogenous RNF138 function also effectively rescues the defective protein expression of EA2 mutants, as well as fully reversing EA2 mutant-induced excessive proteasomal degradation of CaV2.1 WT subunits. RNF138-H36E coexpression only partially restores the dominant-negative effect of EA2 mutants on CaV2.1 WT functional expression, which can be attributed to defective membrane trafficking of CaV2.1 WT in the presence of EA2 mutants. We propose that RNF138 plays a critical role in the homeostatic regulation of CaV2.1 protein level and functional expression and that RNF138 serves as the primary E3 ubiquitin ligase promoting EA2-associated aberrant degradation of human CaV2.1 subunits.SIGNIFICANCE STATEMENTLoss-of-function mutations in the human CaV2.1 subunit are linked to episodic ataxia type 2 (EA2), a dominantly inherited disease characterized by paroxysmal attacks of ataxia and nystagmus. EA2-causing mutants may exert dominant-negative effects on the CaV2.1 wild-type subunit via aberrant proteasomal degradation. The molecular nature of the CaV2.1 ubiquitin–proteasome degradation pathway is currently unknown. The present study reports the first identification of an E3 ubiquitin ligase for CaV2.1, RNF138. CaV2.1 protein stability is dynamically regulated by RNF138 and auxiliary α2δ and β subunits. We provide a proof of concept that protecting the human CaV2.1 subunit from excessive proteasomal degradation with specific interruption of endogenous RNF138 function may partially contribute to the future development of a novel therapeutic strategy for EA2 patients.

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Section: Interaction and Colocalization Of Rnf138 With Ca V 21 In Nementioning

confidence: 99%

mentioning

confidence: 99%

Ubiquitin Ligase RNF138 Promotes Episodic Ataxia Type 2-Associated Aberrant Degradation of Human Ca_v2.1 (P/Q-Type) Calcium Channels

Fu¹,

Jeng

Ma³

et al. 2017

J. Neurosci.

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“…New treatments that target the F508del mutation through the use of potentiators and correctors of chloride channels are being developed in the care of cystic fibrosis-related lung pathology [138]. Certain small-molecule Bcorrector Bcompounds have been shown to partially rescue the functional expression of F508del-CFTR on the membrane of epithelia in patientderived airway cultures, providing the rationale for clinical trials of the best compounds, including VX-809 (Lumacaftor) [139,140].…”

Section: Current and Emerging Novel Therapiesmentioning

confidence: 99%

Bone disease in cystic fibrosis: new pathogenic insights opening novel therapies

Jacquot

Delion²,

Gangloff³

et al. 2015

Osteoporos Int

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Mutations within the gene encoding for the chloride ion channel cystic fibrosis transmembrane conductance regulator (CFTR) results in cystic fibrosis (CF), the most common lethal autosomal recessive genetic disease that causes a number of long-term health problems, as the bone disease. Osteoporosis and increased vertebral fracture risk associated with CF disease are becoming more important as the life expectancy of patients continues to improve. The etiology of low bone density is multifactorial, most probably a combination of inadequate peak bone mass during puberty and increased bone losses in adults. Body mass index, male sex, advanced pulmonary disease, malnutrition and chronic therapies are established additional risk factors for CF-related bone disease (CFBD). Consistently, recent evidence has confirmed that CFTR plays a major role in the osteoprotegerin (OPG) and COX-2 metabolite prostaglandin E2 (PGE2) production, two key regulators in the bone formation and regeneration. Several others mechanisms were also recognized from animal and cell models contributing to malfunctions of osteoblast (cell that form bone) and indirectly of bone-resorpting osteoclasts. Understanding such mechanisms is crucial for the development of therapies in CFBD. Innovative therapeutic approaches using CFTR modulators such as C18 have recently shown in vitro capacity to enhance PGE2 production and normalized the RANKL-to-OPG ratio in human osteoblasts bearing the mutation F508del-CFTR and therefore potential clinical utility in CFBD. This review focuses on the recently identified pathogenic mechanisms leading to CFBD and potential future therapies for treating CFBD.

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“…As a disease caused by a single defective gene, CF airway disease is ideal for treatment with gene therapy (Lee et al, 2005). However, over 20 years have elapsed since the discovery of the CF transmembrane conductance regulator and the associated CFTR gene, and still, no viable gene therapy option exists for curing or alleviating airway disease (Birault et al, 2013). A number of obstacles to gene therapy for CF exist (Ferrari et al, 2002;Oakland et al, 2012), but one major obstacle has yet to be extensively studied: how an active respiratory infection affects gene transfer in the airway.…”

Section: Introductionmentioning

confidence: 99%

In VivoEvaluation of Adeno-Associated Virus Gene Transfer in Airways of Mice with Acute or Chronic Respiratory Infection

et al. 2014

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Patients with cystic fibrosis (CF) often suffer chronic lung infection with concomitant inflammation, a setting that may reduce the efficacy of gene transfer. While gene therapy development for CF often involves viralbased vectors, little is known about gene transfer in the context of an infected airway. In this study, three mouse models were established to evaluate adeno-associated virus (AAV) gene transfer in such an environment. Bordetella bronchiseptica RB50 was used in a chronic, nonlethal respiratory infection in C57BL/6 mice. An inoculum of *10 5 CFU allowed B. bronchiseptica RB50 to persist in the upper and lower respiratory tracts for at least 21 days. In this infection model, administration of an AAV vector on day 2 resulted in 2.8-fold reduction of reporter gene expression compared with that observed in uninfected controls. Postponement of AAV administration to day 14 resulted in an even greater (eightfold) reduction of reporter gene expression, when compared with uninfected controls. In another infection model, Pseudomonas aeruginosa PAO1 was used to infect surfactant protein D (SP-D) or surfactant protein A (SP-A) knockout (KO) mice. With an inoculum of *10 5 CFU, infection persisted for 2 days in the nasal cavity of either mouse model. Reporter gene expression was approximately *2.5-fold lower compared with uninfected mice. In the SP-D KO model, postponement of AAV administration to day 9 postinfection resulted in only a two fold reduction in reporter gene expression, when compared with expression seen in uninfected controls. These results confirm that respiratory infections, both ongoing and recently resolved, decrease the efficacy of AAV-mediated gene transfer.

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Correctors of the basic trafficking defect of the mutant F508del-CFTR that causes cystic fibrosis

Cited by 31 publications

References 40 publications

Ubiquitin Ligase RNF138 Promotes Episodic Ataxia Type 2-Associated Aberrant Degradation of Human Ca_v2.1 (P/Q-Type) Calcium Channels

Ubiquitin Ligase RNF138 Promotes Episodic Ataxia Type 2-Associated Aberrant Degradation of Human Ca_v2.1 (P/Q-Type) Calcium Channels

Bone disease in cystic fibrosis: new pathogenic insights opening novel therapies

In VivoEvaluation of Adeno-Associated Virus Gene Transfer in Airways of Mice with Acute or Chronic Respiratory Infection

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Correctors of the basic trafficking defect of the mutant F508del-CFTR that causes cystic fibrosis

Cited by 31 publications

References 40 publications

Ubiquitin Ligase RNF138 Promotes Episodic Ataxia Type 2-Associated Aberrant Degradation of Human Cav2.1 (P/Q-Type) Calcium Channels

Ubiquitin Ligase RNF138 Promotes Episodic Ataxia Type 2-Associated Aberrant Degradation of Human Cav2.1 (P/Q-Type) Calcium Channels

Bone disease in cystic fibrosis: new pathogenic insights opening novel therapies

In VivoEvaluation of Adeno-Associated Virus Gene Transfer in Airways of Mice with Acute or Chronic Respiratory Infection

Contact Info

Product

Resources

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Ubiquitin Ligase RNF138 Promotes Episodic Ataxia Type 2-Associated Aberrant Degradation of Human Ca_v2.1 (P/Q-Type) Calcium Channels

Ubiquitin Ligase RNF138 Promotes Episodic Ataxia Type 2-Associated Aberrant Degradation of Human Ca_v2.1 (P/Q-Type) Calcium Channels