VX-809 corrects folding defects in cystic fibrosis transmembrane conductance regulator protein through action on membrane-spanning domain 1

Ren, Hong Yu; Grove, Diane E.; Oxana, De La Rosa,; Houck, Scott A.; Sopha, Pattarawut; Goor, Fredrick Van; Hoffman, Beth J.; Cyr, Douglas M.

doi:10.1091/mbc.e13-05-0240

Cited by 261 publications

(360 citation statements)

References 42 publications

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“…To further confirm the critical role of altered CFTR expression, we used VX-809 (Lumacaftor) to correct the folding and increase the amount of channels that was delivered to the cell surface 31 . We treated IB3-1 cells with 5 mM VX-809 for 48 h, and CFTR function was tested using a DiSBAC 2 (bis-(1,3-diethylthiobarbituric acid)trimethine oxonol) probe.…”

Section: Resultsmentioning

confidence: 99%

Mitochondrial Ca2+-dependent NLRP3 activation exacerbates the Pseudomonas aeruginosa-driven inflammatory response in cystic fibrosis

et al. 2015

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The common pathological manifestation of cystic fibrosis (CF) is associated with an excessive lung inflammatory response characterized by interleukin-1b accumulation. CF airway epithelial cells show an exacerbated pro-inflammatory response to Pseudomonas aeruginosa; however, it is unclear whether this heightened inflammatory response is intrinsic to cells lacking CF transmembrane conductance regulator (CFTR). Here we demonstrate that the degree and quality of the inflammatory response in CF are supported by P. aeruginosadependent mitochondrial perturbation, in which flagellin is the inducer and mitochondrial Ca 2 þ uniporter (MCU) is a signal-integrating organelle member for NLRP3 activation and IL-1b and IL-18 processing. Our work elucidates the regulation of the NLRP3 inflammasome by mitochondrial Ca 2 þ in the P. aeruginosa-dependent inflammatory response and deepens our understanding of the significance of mitochondria in the Ca 2 þ -dependent control of inflammation. hronic airway infection by Pseudomonas aeruginosa is a common pathological manifestation in cystic fibrosis (CF) patients, and the role of calcium ions (Ca 2 þ ) in this process seems pivotal in controlling the P. aeruginosa-dependent innate immune response 1 . This manifestation is associated with an excessive inflammatory response characterized by the accumulation of large amounts of cytokines, including interleukin-1b (IL-1b) 2 .Previous studies support the role of IL-1b in the pathogenesis of CF inflammatory lung disease. The levels of IL-1b are increased in bronchoalveolar lavage fluid of CF patients 2,3 , and polymorphisms in the IL-1b gene have been associated with varying degrees of disease severity 4 .The maturation of IL-1b and IL-18 are directed by the caspase-1 (casp-1)-activating multiprotein platform, the inflammasome. Four distinct inflammasomes that contain a nucleotidebinding and oligomerization domain (NOD)-like receptor have been identified: NLRP1, IPAF, NLRP3 and AIM2 (ref. 5). NODlike receptors (NLRs) are intracellular pattern-recognition receptors that recognize pathogen-associated molecular patterns and activate the pro-inflammatory response through specific pathways 6 . It is generally accepted that the release of IL-1b and IL-18 require two distinct signals; however, the nature of these signals during inflammation is not completely defined. Studies indicate that the 'first signal' can be triggered by various pathogen-associated molecular patterns following Toll-like receptor (TLR) activation, which induces the synthesis of proIL-1b and proIL-18. The 'second signal' is provided by activation of the inflammasome and casp-1, leading to IL-1b and IL-18 processing.P. aeruginosa reportedly activates IPAF, leading to IL-1b processing 7 . IPAF interacts directly with procaspase-1, which contains the N-terminal caspase recruitment domain 8 . However, maximum casp-1 activation in response to IPAF agonists requires the involvement of apoptosis-associated specklike protein (ASC) 9,10 , a bipartite, caspase recruitment domainand py...

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Section: Resultsmentioning

confidence: 99%

Mitochondrial Ca2+-dependent NLRP3 activation exacerbates the Pseudomonas aeruginosa-driven inflammatory response in cystic fibrosis

et al. 2015

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“…An interesting question in CF is whether the new class of drugs designed to facilitate folding/biogenesis of CFTR, such as Lumacaftor, influence stress in the ER 61, 62. Lumacaftor is a chaperone type drug that is designed to aid folding in the ER to enhance release of mutant CFTR to the cell surface where it has partial ion channel function.…”

Section: Oxidative and Er Stress In Chronic Inflammatory And Mucopurumentioning

confidence: 99%

Oxidative and endoplasmic reticulum stress in respiratory disease

2018

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Oxidative stress and endoplasmic reticulum (ER) stress are related states that can occur in cells as part of normal physiology but occur frequently in diseases involving inflammation. In this article, we review recent findings relating to the role of oxidative and ER stress in the pathophysiology of acute and chronic nonmalignant diseases of the lung, including infections, cystic fibrosis, idiopathic pulmonary fibrosis and asthma. We also explore the potential of drugs targeting oxidative and ER stress pathways to alleviate disease.

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“…[12][13][14][15] The most common mutation in Europe and North America, p.Phe508del, has been studied extensively and has been found to impair CFTR protein folding during synthesis. [16][17][18][19] Knowledge regarding the molecular defects caused by p.Phe508del has driven the development of targeted, interventional compounds, such as VX-809 (or Lumacaftor). Although VX-809 has shown promise in partially ameliorating the protein folding defect caused by p.Phe508del in vitro, it is yet to be determined if it will have clinical efficacy in combination with VX-770 in a phase III clinical trial.…”

mentioning

confidence: 99%

Genetic, cell biological, and clinical interrogation of theCFTR mutation c.3700 A>G (p.Ile1234Val) informs strategies for future medical intervention

Molinski

Gonska

Huan

et al. 2014

Genetics in Medicine

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VX-809 corrects folding defects in cystic fibrosis transmembrane conductance regulator protein through action on membrane-spanning domain 1

Cited by 261 publications

References 42 publications

Mitochondrial Ca2+-dependent NLRP3 activation exacerbates the Pseudomonas aeruginosa-driven inflammatory response in cystic fibrosis

Mitochondrial Ca2+-dependent NLRP3 activation exacerbates the Pseudomonas aeruginosa-driven inflammatory response in cystic fibrosis

Oxidative and endoplasmic reticulum stress in respiratory disease

Genetic, cell biological, and clinical interrogation of theCFTR mutation c.3700 A>G (p.Ile1234Val) informs strategies for future medical intervention

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