Human ABCA3, a product of a responsible gene for abca3 for fatal surfactant deficiency in newborns, exhibits unique ATP hydrolysis activity and generates intracellular multilamellar vesicles

Nagata, Kazuto; Yamamoto, Akira; Ban, Nobuhiro; Tanaka, Akihiro; Matsuo, Masaru; Kioka, Noriyuki; Inagaki, Nobuya; Ueda, Kazumitsu

doi:10.1016/j.bbrc.2004.09.043

Cited by 73 publications

(69 citation statements)

References 29 publications

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“…23 In vitro, ABCA3 is necessary, but not sufficient for the formation of mature lamellar bodies in alveolar cells, leading to the concept that, in addition to ABCA3, other surfactant proteins such as SP-B are required for the transition of lysosomes to distinct lamellar bodies. 10,24 Besides its function in the lungs, several reports also provided first evidence of a possible role of ABCA3 in cancer cell drug resistance. In a matched pair analysis on a panel of 22 cell lines and their resistant variants on the genomic level, ABCA3 was found to be overexpressed in three resistant variants with an increase in gene copy numbers as the mechanism of ABCA3 abundance.…”

Section: Discussionmentioning

confidence: 99%

Intracellular ABC transporter A3 confers multidrug resistance in leukemia cells by lysosomal drug sequestration

et al. 2008

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Section: Discussionmentioning

confidence: 99%

Intracellular ABC transporter A3 confers multidrug resistance in leukemia cells by lysosomal drug sequestration

et al. 2008

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“…8 ABCA3 is a regulator of lamellar body metabolism and was reported to form lipid containing vesicles in human embryonic kidney cells. 45 Little is known about the physiological function of the ABCA6-like transporters including ABCA6, ABCA9, ABCA10. The members of this subclass were reported to be regulated by cholesterol inversely to ABCA1 and therefore to act in opposed pathways.…”

Section: Discussionmentioning

confidence: 99%

Gene expression profiling of ABC transporters in dermal fibroblasts of pseudoxanthoma elasticum patients identifies new candidates involved in PXE pathogenesis

Hendig

Langmann

Kocken

et al. 2008

Laboratory Investigation

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Mutations in the ABCC6 gene, encoding the multidrug resistance-associated protein 6 (MRP6), cause pseudoxanthoma elasticum (PXE). This heritable disorder leads to pathological alterations in connective tissues. The implication of MRP6 deficiency in PXE is still unknown. Moreover, nothing is known about a possible compensatory expression of other ATP binding-cassette (ABC) transporter proteins in MRP6-deficient cells. We investigated the gene expression profile of 47 ABC transporters in human dermal fibroblasts of healthy controls (n ¼ 2) and PXE patients (n ¼ 4) by TaqMan low-density array. The analysis revealed the expression of 37 ABC transporter genes in dermal fibroblasts. ABCC6 gene expression was not quantifiable in fibroblasts derived from PXE patients. Seven genes (ABCA6, ABCA9, ABCA10, ABCB5, ABCC2, ABCC9 and ABCD2) were induced, whereas the gene expression of one gene (ABCA3) was decreased, comparing controls and PXE patients (with at least twofold changes). We reanalyzed the gene expression of selected ABC transporters in a larger set of dermal fibroblasts from controls and PXE patients (n ¼ 6, each). Reanalysis showed high interindividual variability between samples, but confirmed the results obtained in the array analysis. The gene expression of ABC transporter genes, as well as lineage markers of PXE, was further examined after inhibition of ABCC6 gene expression by using specific small-interfering RNA. These experiments corroborated the observed gene expression alterations, most notably in the ABCA subclass (up to fourfold, Po0.05). We therefore conclude that MRP6-deficient dermal fibroblasts exhibit a distinct gene expression profile of ABCA transporters, potentially to compensate for MRP6 deficiency. Moreover, our results point to a function for ABCC6/MRP6 in sterol transport, as sterols are preferential regulators of ABCA transporter activity and expression. Further studies are now required to uncover the role of ABCA transporters in PXE.

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“…1B). ABCA3 is expressed as 190-and 150-kDa forms, with the latter suggested to be produced by proteolytic cleavage at extracellular domain 1 (ECD1) within lysosomal vesicles (21,36). In native lung tissue, the cleaved form is predominant, whereas both forms are detected when overexpressed in cultured cells.…”

Section: Subcellular Localization and Glycosylation Of Abca3-gfp And mentioning

confidence: 99%

“…ABCA3 is expressed predominantly at the limiting membrane of the lamellar bodies in lung alveolar type II cells and is proposed to be a surfactant lipid transporter (20,36). Exogenous expression of ABCA3 in cultured cells promotes lipid uptake into intracellular vesicles that generate lamellar body-like vesicles (7,18,21). ABCA3 deficiency in human and mice leads to decreased phosphatidylcholine and phosphatidylglycerol in surfactant, dysgenesis of lamellar bodies, and respiratory distress (1,3,8,11,12,27).…”

mentioning

confidence: 99%

Aberrant catalytic cycle and impaired lipid transport into intracellular vesicles in ABCA3 mutants associated with nonfatal pediatric interstitial lung disease

Matsumura¹,

Ban²,

Inagaki³

2008

American Journal of Physiology-Lung Cellular and Molecular Phys

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However, the mechanisms underlying the less severe phenotype of patients with ABCA3 mutation are unclear. In this study, we characterized ABCA3 mutant proteins identified in pediatric interstitial lung disease (pILD). E292V (intracellular loop 1), E690K (adjacent to Walker B motif in nucleotide binding domain 1), and T1114M (8th putative transmembrane segment) mutant proteins are localized mainly in intracellular vesicle membranes as wild-type protein. Lipid analysis and sucrose gradient fractionation revealed that the transport function of E292V mutant protein is moderately preserved, whereas those of E690K and T1114M mutant proteins are severely impaired. Vanadate-induced nucleotide trapping and photoaffinity labeling of wild-type and mutant proteins using 8-azido-[ 32 P]ATP revealed an aberrant catalytic cycle in these mutant proteins. These results demonstrate the importance of a functional catalytic cycle in lipid transport of ABCA3 and suggest a pathophysiological mechanism of pILD due to ABCA3 mutation.

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Human ABCA3, a product of a responsible gene for abca3 for fatal surfactant deficiency in newborns, exhibits unique ATP hydrolysis activity and generates intracellular multilamellar vesicles

Cited by 73 publications

References 29 publications

Intracellular ABC transporter A3 confers multidrug resistance in leukemia cells by lysosomal drug sequestration

Intracellular ABC transporter A3 confers multidrug resistance in leukemia cells by lysosomal drug sequestration

Gene expression profiling of ABC transporters in dermal fibroblasts of pseudoxanthoma elasticum patients identifies new candidates involved in PXE pathogenesis

Aberrant catalytic cycle and impaired lipid transport into intracellular vesicles in ABCA3 mutants associated with nonfatal pediatric interstitial lung disease

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