Adrenoleukodystrophy: subcellular localization and degradation of adrenoleukodystrophy protein (ALDP/ABCD1) with naturally occurring missense mutations

Takahashi, Norimasa; Morita, Masashi; Maeda, Takanori; Harayama, Yuta; Shimozawa, Nobuyuki; Suzuki, Yasuyuki; Furuya, Hirokazu; Sato, Ryuichiro; Kashiwayama, Yoshinori; Imanaka, Tsuneo

doi:10.1111/j.1471-4159.2007.04457.x

Cited by 25 publications

(28 citation statements)

References 45 publications

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“…Although we and others have shown that missense X-ALD mutations result in ALDP instability in mammalian cells [56,58] (Figure 4), in a previous study, we noticed that cts mutants which have 'protein-absent', disease-associated equivalents in human ABCD1 were expressed as stable correctly targeted proteins in Arabidopsis [46]. We therefore tested whether ALDP variants bearing missense mutations which result in protein mistargeting or instability in mammalian cells would behave similarly when expressed in plant cells.…”

Section: X-ald Mutant Proteins Are Expressed At the Peroxisome In Plamentioning

confidence: 92%

“…We therefore tested whether ALDP variants bearing missense mutations which result in protein mistargeting or instability in mammalian cells would behave similarly when expressed in plant cells. In addition to the temperature-sensitive mutants identified above, a range of X-ALD mutants with different intracellular fates was selected [58] ( Table 2), with the goal of comparing the capacity of plant and mammalian cells for sensing and turnover of defective peroxisomal membrane proteins. These included relatively common mutants which are unstable in fibroblasts, but which can be rescued by the application of proteasome inhibitors (p.Ser606Leu, p.Arg617His and p.His667Asp), the p.Arg104Cys mutant in which degradation of ALDP cannot be prevented by proteasome inhibitors and the p.Tyr174Cys mutant which is Table 2 …”

Section: X-ald Mutant Proteins Are Expressed At the Peroxisome In Plamentioning

confidence: 99%

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Conservation of targeting but divergence in function and quality control of peroxisomal ABC transporters: an analysis using cross-kingdom expression

Zhang

Lousa

Schutte-Lensink

et al. 2011

Biochemical Journal

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ABC (ATP-binding cassette) subfamily D transporters are found in all eukaryotic kingdoms and are known to play essential roles in mammals and plants; however, their number, organization and physiological contexts differ. Via cross-kingdom expression experiments, we have explored the conservation of targeting, protein stability and function between mammalian and plant ABCD transporters. When expressed in tobacco epidermal cells, the mammalian ABCD proteins ALDP (adrenoleukodystrophy protein), ALDR (adrenoleukodystrophy-related protein) and PMP70 (70 kDa peroxisomal membrane protein) targeted faithfully to peroxisomes and P70R (PMP70-related protein) targeted to the ER (endoplasmic reticulum), as in the native host. The Arabidopsis thaliana peroxin AtPex19_1 interacted with human peroxisomal ABC transporters both in vivo and in vitro, providing an explanation for the fidelity of targeting. The fate of X-linked adrenoleukodystrophy disease-related mutants differed between fibroblasts and plant cells. In fibroblasts, levels of ALDP in some 'protein-absent' mutants were increased by lowtemperature culture, in some cases restoring function. In contrast, all mutant ALDP proteins examined were stable and correctly targeted in plant cells, regardless of their fate in fibroblasts. ALDR complemented the seed germination defect of the Arabidopsis cts-1 mutant which lacks the peroxisomal ABCD transporter CTS (Comatose), but neither ALDR nor ALDP was able to rescue the defect in fatty acid β-oxidation in establishing seedlings. Taken together, our results indicate that the mechanism for trafficking of peroxisomal membrane proteins is shared between plants and mammals, but suggest differences in the sensing and turnover of mutant ABC transporter proteins and differences in substrate specificity and/or function.

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Section: X-ald Mutant Proteins Are Expressed At the Peroxisome In Plamentioning

confidence: 92%

Section: X-ald Mutant Proteins Are Expressed At the Peroxisome In Plamentioning

confidence: 99%

Conservation of targeting but divergence in function and quality control of peroxisomal ABC transporters: an analysis using cross-kingdom expression

Zhang

Lousa

Schutte-Lensink

et al. 2011

Biochemical Journal

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“…Indeed misfolded peroxisomal ABC transporters are subject to quality control, as revealed by missense mutations associated with X-ALD, the majority of which result in markedly reduced protein levels at the peroxisome membrane ). The precise quality control mechanisms remain to be investigated but the existence of several checkpoints has been suggested (Takahashi et al 2007). Interestingly, X-ALD mutants which were subject to proteasomal degradation in human fibroblasts were correctly targeted and stable when expressed in plant cells, an effect which was not wholly explicable by low temperature rescue of protein folding .…”

Section: Targetingmentioning

confidence: 99%

Plant Peroxisomal ABC Transporters: Flexible and Unusual

Theodoulou

Baldwin

et al. 2014

Signaling and Communication in Plants

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ABC transporters of subfamily D mediate import of substrates for β-oxidation into peroxisomes. Whilst mammals possess three peroxisomal ABCD proteins which homodimerise to form transporters with distinct substrate specificities, Baker's yeast has a single transporter formed by heterodimerisation, which imports long-chain fatty acyl CoAs. Plants have a single-fused heterodimer transporter that exhibits broad substrate specificity, reflecting the wide range of β-oxidation substrates processed by plants. The fusion appears to have occurred early in the evolution of land plants and was followed by an early duplication event in the monocot lineage. Plant ABCD proteins function in all stages of the life cycle and their physiological roles reflect the ability to transport diverse substrates including saturated and unsaturated fatty acids and aromatic compounds such as precursors of hormones and secondary metabolites. Recent work suggests that transport of CoA substrates involves their cleavage and re-esterification within the peroxisome, thus interaction with appropriate acyl adenylate-activating enzymes potentially provides a mechanism for regulating entry of different substrates into β-oxidation. The mechanism of ABCD transporter targeting is broadly conserved across kingdoms but evidence suggests the regulation of protein turnover differs.

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“…22) ABCD1 cDNA was cloned into pcDNA4HisMax vector by TA-cloning. The human ABCD1 gene in pcDNA3.1+ / ABCD1 (kindly provided by Dr. K. Kamijo, Tohoku University) was used as the template.…”

Section: Methodsmentioning

confidence: 99%

“…24) Immunofluorescence analysis was performed as described previously. 22) Human glioblastoma U87 cells were seeded on dishes containing coverslips in EMEM with 10% FBS. The cells on the coverslips were washed three times in PBS and fixed with 3% formaldehyde in PBS for 20 min.…”

Section: Methodsmentioning

confidence: 99%

Very Long Chain Fatty Acid β-Oxidation in Astrocytes: Contribution of the ABCD1-Dependent and -Independent Pathways

Morita

Shinbo

Asahi

et al. 2012

Biological & Pharmaceutical Bulletin

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Very long chain fatty acid (VLCFA) metabolism in astrocytes is important for the maintenance of myelin structure in central nervous system. To analyze the contribution of the ABCD1-dependent and -independent pathways to VLCFA metabolism in astrocytes, we prepared human glioblastoma U87 cells with a silencing of ABCD1 and primary astrocytes from abcd1-deficient mice, and measured fatty acid β-oxidation in the presence or absence of a potent inhibitor of carnitine palmitoyltransferase I, 2-[5-(4-chlorophenyl)pentyl]oxirane-2-carboxylate (POCA). In U87 cells, C24:0 β-oxidation was decreased to ca. 70% of the control in the presence of POCA, and the activity was further decreased to ca. 20% by the silencing of ABCD1. In mouse primary astrocytes, C24:0 β-oxidation was also decreased to ca. 70% of the control in the presence of POCA. The C24:0 β-oxidation in Abcd1-deficient primary astrocytes was ca. 60% of the wild-type cells and the activity was further decreased to ca. 25% in the presence of POCA. Compared to human skin fibroblasts, in which VLCFA β-oxidation is not significantly inhibited by POCA, approximately one-third of the overall VLCFA β-oxidation was inhibited in both types of astrocytic cells. These results suggest that VLCFA is indeed β-oxidized in ABCD1-dependent pathway, but the ABCD1-independent peroxisomal and mitochondrial β-oxidation pathways significantly contribute to VLCFA β-oxidation in astrocytic cells.Key words very long chain fatty acid β-oxidation; astrocyte; ABCD1; peroxisome; mitochondria Peroxisomes are single membrane organelles that are present in almost all eukaryotic cells. The peroxisomes are involved in a variety of metabolic processes, including the β-oxidation of fatty acids, especially very long chain fatty acids (VLCFA, >C22), and the synthesis of ether phospholipids and bile acids in mammals.1) Transport of substrates for fatty acid β-oxidation across the peroxisomal membrane is an essential step in this metabolism. Peroxisomal ATP-binding cassette (ABC) proteins have been implicated in this transport.To date, three ABC proteins, classified into "subfamily D," have been identified in mammalian peroxisomes. These are adrenoleukodystrophy protein (ALDP/ABCD1),2) ALDP-related protein (ALDRP/ABCD2) 3) and a 70-kDa peroxisomal membrane protein (PMP70/ABCD3). 4) Dysfunction of ABCD1 causes the human genetic disorder X-linked adrenoleukodystrophy (X-ALD) characterized by an accumulation of VLCFA because of the impaired peroxisomal β-oxidation of VLCFA.5) VLCFA β-oxidation in X-ALD patient fibroblasts was restored by the expression of ABCD1. Likewise, the expression of ABCD2, which has a high sequence similarity to ABCD1, also restored VLCFA β-oxidation in X-ALD fibro blasts.6) In analogy to the role of Pxa1p/Pxa2p, 7) yeast peroxisomal half-ABC transporters, which is involved in the transport of acyl-CoA, ABCD1 and ABCD2 are thought to be involved in the metabolic transport of VLCFA-CoA. 8,9) ABCD3 is suggested to be involved in the metabolic transport of long chain fatty acids (LCFA)...

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Adrenoleukodystrophy: subcellular localization and degradation of adrenoleukodystrophy protein (ALDP/ABCD1) with naturally occurring missense mutations

Cited by 25 publications

References 45 publications

Conservation of targeting but divergence in function and quality control of peroxisomal ABC transporters: an analysis using cross-kingdom expression

Conservation of targeting but divergence in function and quality control of peroxisomal ABC transporters: an analysis using cross-kingdom expression

Plant Peroxisomal ABC Transporters: Flexible and Unusual

Very Long Chain Fatty Acid β-Oxidation in Astrocytes: Contribution of the ABCD1-Dependent and -Independent Pathways

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