Some ABCA3 mutations elevate ER stress and initiate apoptosis of lung epithelial cells

Weichert, Nina; Kaltenborn, Eva; Hector, Andreas; Woischnik, Markus; Schams, Andrea; Holzinger, Andreas; Kern, Sunčana; Griese, Matthias

doi:10.1186/1465-9921-12-4

Cited by 86 publications

(81 citation statements)

References 44 publications

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“…Similarly, single point variants in the ABCA3 gene can reduce the expression of mature protein, presumably by increasing endoplasmic reticulum (ER)-associated degradation of misfolded protein (28). Beyond the neonatal period, infants carrying a single R288K variant of ABCA3 may be more vulnerable to lung injury affecting the alveolar space, resulting in an increased risk of chronic pediatric ILD involving surfactant dysfunction.…”

Section: Resultsmentioning

confidence: 99%

Increased Risk of Interstitial Lung Disease in Children with a Single R288K Variant of ABCA3

Wittmann¹,

Frixel²,

Höppner³

et al. 2016

Mol Med

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Section: Resultsmentioning

confidence: 99%

Increased Risk of Interstitial Lung Disease in Children with a Single R288K Variant of ABCA3

Wittmann¹,

Frixel²,

Höppner³

et al. 2016

Mol Med

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“…ER stressinduced cell death has also been reported in adult lungs, secondary to oxidative stress attributable to cigarette-smoke exposure and/or chronic obstructive pulmonary disease (37)(38)(39)(40). Interestingly, most reports on adult lungs have implicated alveolar epithelial cells (34,(39)(40)(41)(42) and the activation of CHOP (34,(38)(39)(40).…”

Section: Discussionmentioning

confidence: 99%

Hyperoxia and Interferon-γ–Induced Injury in Developing Lungs Occur via Cyclooxygenase-2 and the Endoplasmic Reticulum Stress–Dependent Pathway

Choo-Wing

Syed

Harijith

et al. 2013

Am J Respir Cell Mol Biol

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We noted a marked increase in cyclooxygenase-2 (Cox2) and the activation of the endoplasmic reticulum (ER) stress pathway in newborn murine lung on exposure to hyperoxia and IFN-g.We soughtto evaluate Cox2-mediated ER stress pathway activation in hyperoxia-induced and IFN-g-mediated injury in developing lungs. We applied in vivo genetic gain-of-function and genetic/chemical inhibition, as well as in vitro lossof-function genetic strategies. Hyperoxia-induced and IFN-g-mediated impaired alveolarization was rescued by Cox2 inhibition, using celecoxib. The use of small interfering RNA against the ER stress pathway mediator, the C/EBP homologous protein (CHOP; also known as growth arrest and DNA damage-inducible gene 153/GADD153), alleviated cell death in alveolar epithelial cells as well as in hyperoxia-induced and IFNg-mediated murine models of bronchopulmonary dysplasia (BPD). In addition, CHOP siRNA also restored alveolarization in the in vivo models. Furthermore, as evidence of clinical relevance, we show increased concentrations of Cox2 and ER stress pathway mediators in human lungs with BPD. Cox2, via CHOP, may significantly contribute to the final common pathway of hyperoxia-induced and IFN-g-mediated injury in developing lungs and human BPD.Keywords: newborn; oxygen; BPD; CHOP; cell deathIn the developing lung, injury attributable to hyperoxic exposure is an important component in the pathogenesis of bronchopulmonary dysplasia (BPD) (1, 2). The immature human lung during the saccular phase is most commonly exposed to such an exogenous insult, and is predisposed to BPD. The final result is a lung phenotype characterized by fewer and larger simplified alveoli (1-4). Hyperoxia-induced lung injury is characterized by an influx of inflammatory cells, along with endothelial and epithelial cell death (5, 6).Cell death is said to be a key initiator of the process of alveolar simplification. The activation of key caspases (3,8,9) and components of the extrinsic/death receptor and intrinsic/ mitochondrial cell death pathways underlies the molecular mechanisms of cell death (5-7). Another cell-death signaling pathway involves the endoplasmic reticulum (ER), which is the site for the folding and assembly of proteins destined for delivery to the extracellular space, plasma membrane, and the exocytic/endocytic compartments (8, 9). When cells are exposed to ER stress, malfolded or unfolded proteins accumulate in the ER lumen, giving rise to a synonymous term, the unfolded protein response (UPR) (8, 9). ER stress is sensed by three ER-resident transmembrane proteins, specifically, inositol-requiring enzyme-1 a (IRE-a), activating transcription factor-6a (ATF6a), and protein kinase regulated by RNA-like ER kinase (PERK), which are freed from binding immunoglobulin protein (BiP; also known as glucoseregulated protein-78, or GRP78) during ER stress (10). Whereas ER stress-induced cell death signaling can occur via multiple pathways, the pathway (i.e., via PERK) that induces transcription of the proapoptotic factor C/EBP homol...

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“…Previous studies have demonstrated two protein bands at 220 and 180 kD that represent noncleaved and cleaved forms of wild-type ABCA3_GFP and a single 220-kD noncleaved band for mutant proteins that disrupt intracellular trafficking (e.g., L101P, type I mutation) (8,9,11). Using immunoblotting of total cellular protein from HEK293T cells transiently transfected with wild-type or mutant ABCA3 plasmid DNA, we observed two bands corresponding to cleaved and noncleaved forms for wild-type, E292V, R288K, and R1474W proteins ( Figure 3).…”

Section: Subcellular Immunofluorescent Localization and Immunoblottingmentioning

confidence: 99%

“…Functional ABCA3 mutations interrupt intracellular trafficking of the protein to the lamellar body (type I) or reduce ATPase activity and impair phospholipid transport into the lamellar body (type II) (8,9). However, fewer than 10% of ABCA3 mutations have been functionally characterized, and the locations of the mutations in the gene or the encoded protein do not reliably predict mutation pathogenicity (8)(9)(10)(11). In silico algorithms can predict mutation-encoded disruption of protein function (12)(13)(14), but require confirmation in a biologic model system to inform clinical decision making.…”

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confidence: 99%

Functional Characterization of ATP-Binding Cassette Transporter A3 Mutations from Infants with Respiratory Distress Syndrome

Wambach

Yang

Wegner

et al. 2016

Am J Respir Cell Mol Biol

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Mutations in the ATP-binding cassette transporter A3 gene (ABCA3) result in severe neonatal respiratory distress syndrome and childhood interstitial lung disease. As most ABCA3 mutations are rare or private, determination of mutation pathogenicity is often based on results from in silico prediction tools, identification in unrelated diseased individuals, statistical association studies, or expert opinion. Functional biologic studies of ABCA3 mutations are needed to confirm mutation pathogenicity and inform clinical decision making. Our objective was to functionally characterize two ABCA3 mutations (p.R288K and p.R1474W) identified among term and latepreterm infants with respiratory distress syndrome with unclear pathogenicity in a genetically versatile model system. We performed transient transfection of HEK293T cells with wild-type or mutant ABCA3 alleles to assess protein processing with immunoblotting. We used transduction of A549 cells with adenoviral vectors, which concurrently silenced endogenous ABCA3 and expressed either wildtype or mutant ABCA3 alleles (p.R288K and p.R1474W) to assess immunofluorescent localization, ATPase activity, and organelle ultrastructure. Both ABCA3 mutations (p.R288K and p.R1474W) encoded proteins with reduced ATPase activity but with normal intracellular localization and protein processing. Ultrastructural phenotypes of lamellar body-like vesicles in A549 cells transduced with mutant alleles were similar to wild type. Mutant proteins encoded by ABCA3 mutations p.R288K and p.R1474W had reduced ATPase activity, a biologically plausible explanation for disruption of surfactant metabolism by impaired phospholipid transport into the lamellar body. These results also demonstrate the usefulness of a genetically versatile, human model system for functional characterization of ABCA3 mutations with unclear pathogenicity.Keywords: surfactant; childhood interstitial lung disease; neonatal respiratory distress; respiratory distress syndrome ATP-binding cassette transporter A3 (ABCA3), a member of a large family of proteins that hydrolyze ATP to transport substances across biologic membranes, is encoded by an 80-kb gene (ABCA3; NM_001089.2, Gene ID 21) and consists of 1,704 amino acids with two membranespanning domains and two nucleotide binding domains. ABCA3 is expressed in alveolar type II cells, localizes to the membranes of lamellar bodies, and transports phospholipids into the lamellar body, where surfactant, a complex protein-phospholipid mixture that reduces surface tension and prevents alveolar collapse at end expiration, is assembled and stored (1-3). ABCA3 is also required for lamellar body biogenesis (4).Biallelic loss-of-function (nonsense, frameshift) mutations in ABCA3 result in severe, progressive neonatal respiratory distress syndrome (RDS) that is lethal by 1 year of age without lung transplantation (5). However, for individuals with missense, T.C., F.V.W., A.H., B.P.H., and F.S.C.; drafting and revising the manuscript for important intellectual content-J.A.W., P.Y....

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Some ABCA3 mutations elevate ER stress and initiate apoptosis of lung epithelial cells

Cited by 86 publications

References 44 publications

Increased Risk of Interstitial Lung Disease in Children with a Single R288K Variant of ABCA3

Increased Risk of Interstitial Lung Disease in Children with a Single R288K Variant of ABCA3

Hyperoxia and Interferon-γ–Induced Injury in Developing Lungs Occur via Cyclooxygenase-2 and the Endoplasmic Reticulum Stress–Dependent Pathway

Functional Characterization of ATP-Binding Cassette Transporter A3 Mutations from Infants with Respiratory Distress Syndrome

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