Syntaxin 1A is expressed in airway epithelial cells, where it modulates CFTR Cl– currents

Naren, Anjaparavanda P.; Di, Anke; Cormet‐Boyaka, Estelle; Boyaka, Prosper N.; McGhee, Jerry R.; Zhou, Weihong; Akagawa, Kimio; Fujiwara, Tomonori; Thomé, Ulrich; Engelhardt, John F.; Nelson, Deborah J.; Kirk, Kevin L.

doi:10.1172/jci8631

Cited by 67 publications

(54 citation statements)

References 35 publications

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“…Evidence of high STX1C expression is in contrast to previous studies reporting solely expression of STX1A in epithelia, 10 a discrepancy that can be explained by the fact that these studies used an antibody not discriminating between STX1A and STX1C. Regrettably, in the literature only STX1A-CFTR interactions have been investigated and described so far, while potential STX1C-CFTR interactions have been neglected probably due to the fact that STX1C expression has mainly aroused interest in the research community in the context of its neuronal expression.…”

Section: Discussioncontrasting

confidence: 99%

“…8,9 Syntaxin 1A (brain) (STX1A) is a t-SNARE protein involved in the fusion of synaptic vesicles and neurotransmitter release. Previous studies have shown that STX1A is expressed in airway and intestinal cells, 10 where it negatively modulates CFTR function by altering intracellular trafficking and/ or channel activity. 11 In addition, STX1A was found to negatively regulate the remaining function of the most common CFTR mutation, p.Phe508del.…”

Section: Introductionmentioning

confidence: 99%

“…11 In addition, STX1A was found to negatively regulate the remaining function of the most common CFTR mutation, p.Phe508del. 10 STX1A consists of 288 amino-acid residues, of which the 23 C-terminal residues serve as membrane anchor. The isoform syntaxin 1C (STX1C) contains an insert of 91 bp at codon 226, leading to a frameshift and subsequently to a truncated protein of 260 residues lacking the transmembrane domain.…”

Section: Introductionmentioning

confidence: 99%

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Clinical and molecular characterization of the potential CF disease modifier syntaxin 1A

et al. 2013

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Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator gene (CFTR). Disease severity in CF varies greatly, and sibling studies strongly indicate that genes other than CFTR modify disease outcome. Syntaxin 1A (STX1A) has been reported as a negative regulator of CFTR and other ion channels. We hypothesized that STX1A variants act as a CF modifier by influencing the remaining function of mutated CFTR. We identified STX1A variants by genomic resequencing patients from the Bernese CF Patient Data Registry and applied linear mixed model analysis to establish genotype-phenotype correlations, revealing STX1A rs4363087 (c.467 À38A4G) to significantly influence lung function. The same STX1A risk allele was recognized in the European CF Twin and Sibling Study (P ¼ 0.0027), demonstrating that the genotype-phenotype association of STX1A to CF disease severity is robust enough to allow replication in two independent CF populations. rs4363087 is in linkage disequilibrium to the exonic variant rs2228607 (c.204C4T). Considering that neither rs4363087 nor rs2228607 changes the amino-acid sequence of STX1A, we investigated their effects on mRNA level. We show that rs2228607 reinforces aberrant splicing of STX1A mRNA, leading to nonsense-mediated mRNA decay. In conclusion, we demonstrate the clinical relevance of STX1A variants in CF, and evidence the functional relevance of STX1A variant rs2228607 at molecular level. Our findings show that genes interacting with CFTR can modify CF disease progression.

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Section: Discussioncontrasting

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Clinical and molecular characterization of the potential CF disease modifier syntaxin 1A

et al. 2013

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“…Streptavidin agarose beads (20 l) were used to capture the biotinylated membranes and subjected to Western blot analysis. Syntaxin 3 was used as an apical marker (18) and Na ϩ -K ϩ -Cl Ϫ Cotransporter (NKCC) was used as a basolateral marker (19).…”

Section: Methodsmentioning

confidence: 99%

A macromolecular complex of β ₂ adrenergic receptor, CFTR, and ezrin/radixin/moesin-binding phosphoprotein 50 is regulated by PKA

Naren

Cobb

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

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It has been demonstrated previously that both the cystic fibrosis transmembrane conductance regulator (CFTR) and ␤2 adrenergic receptor (␤2AR) can bind ezrin͞radixin͞moesin-binding phosphoprotein 50 (EBP50, also referred to as NHERF) through their PDZ motifs. Here, we show that ␤2 is the major adrenergic receptor isoform expressed in airway epithelia and that it colocalizes with CFTR at the apical membrane. ␤2AR stimulation increases CFTR activity, in airway epithelial cells, that is glybenclamide sensitive. Deletion of the PDZ motif from CFTR uncouples the channel from the receptor both physically and functionally. This uncoupling is specific to the ␤2AR receptor and does not affect CFTR coupling to other receptors (e.g., adenosine receptor pathway). Biochemical studies demonstrate the existence of a macromolecular complex involving CFTR-EBP50-␤ 2AR through PDZ-based interactions. Assembly of the complex is regulated by PKA-dependent phosphorylation. Deleting the regulatory domain of CFTR abolishes PKA regulation of complex assembly. This report summarizes a macromolecular signaling complex involving CFTR, the implications of which may be relevant to CFTR-dysfunction diseases.

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“…Syntaxin 1A is a t-SNARE that is highly expressed in neurons and, to a lesser extent, in a variety of epithelial cells (5). Together with SNAP-25 (another t-SNARE) and VAMP-2/synaptobrevin (a v-SNARE), syntaxin 1A assembles into core SNARE complexes that regulate membrane fusion at the presynaptic membrane in neurons.…”

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confidence: 99%

The Interaction between Syntaxin 1A and Cystic Fibrosis Transmembrane Conductance Regulator Cl− Channels Is Mechanistically Distinct from Syntaxin 1A-SNARE Interactions

Ganeshan¹,

Di²,

Nelson³

et al. 2003

Journal of Biological Chemistry

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Syntaxin 1A binds to and inhibits epithelial cystic fibrosis transmembrane conductance regulator (CFTR) Cl ؊ channels and synaptic Ca 2؉ channels in addition to participating in SNARE complex assembly and membrane fusion. We exploited the isoform-specific nature of the interaction between syntaxin 1A and CFTR to identify residues in the H3 domain of this SNARE (SNARE motif) that influence CFTR binding and regulation. Mutating isoform-specific residues that map to the surface of syntaxin 1A in the SNARE complex led to the identification of two sets of hydrophilic residues that are important for binding to and regulating CFTR channels or for binding to the syntaxin regulatory protein Munc-18a. None of these mutations affected syntaxin 1A binding to other SNAREs or the assembly and stability of SNARE complexes in vitro. Conversely, the syntaxin 1A-CFTR interaction was unaffected by mutating hydrophobic residues in the H3 domain that influence SNARE complex stability and Ca 2؉ channel regulation. Thus, CFTR channel regulation by syntaxin 1A involves hydrophilic interactions that are mechanistically distinct from the hydrophobic interactions that mediate SNARE complex formation and Ca 2؉ channel regulation by this t-SNARE.

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Syntaxin 1A is expressed in airway epithelial cells, where it modulates CFTR Cl– currents

Cited by 67 publications

References 35 publications

Clinical and molecular characterization of the potential CF disease modifier syntaxin 1A

Clinical and molecular characterization of the potential CF disease modifier syntaxin 1A

A macromolecular complex of β ₂ adrenergic receptor, CFTR, and ezrin/radixin/moesin-binding phosphoprotein 50 is regulated by PKA

The Interaction between Syntaxin 1A and Cystic Fibrosis Transmembrane Conductance Regulator Cl− Channels Is Mechanistically Distinct from Syntaxin 1A-SNARE Interactions

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Syntaxin 1A is expressed in airway epithelial cells, where it modulates CFTR Cl– currents

Cited by 67 publications

References 35 publications

Clinical and molecular characterization of the potential CF disease modifier syntaxin 1A

Clinical and molecular characterization of the potential CF disease modifier syntaxin 1A

A macromolecular complex of β 2 adrenergic receptor, CFTR, and ezrin/radixin/moesin-binding phosphoprotein 50 is regulated by PKA

The Interaction between Syntaxin 1A and Cystic Fibrosis Transmembrane Conductance Regulator Cl− Channels Is Mechanistically Distinct from Syntaxin 1A-SNARE Interactions

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A macromolecular complex of β ₂ adrenergic receptor, CFTR, and ezrin/radixin/moesin-binding phosphoprotein 50 is regulated by PKA