Peroxisomal Membrane Ghosts in Zellweger Syndrome—Aberrant Organelle Assembly

Santos, M.J.; Imanaka, Tsuneo; Shio, H; Gm, Small; Pb, Lazarow

doi:10.1126/science.3281254

Cited by 318 publications

(210 citation statements)

References 28 publications

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“…Independent biochemical analysis with flotation gradients confirmed the presence of vesicular structures containing both peroxisomal matrix and membrane proteins in the PEX23 gene disruption strain pex23KOA. Because these vesicles contain both peroxisomal matrix and membrane proteins, they are not classic "peroxisome ghosts," which, as originally defined, are membranous structures containing peroxisomal membrane proteins but lacking peroxisomal matrix proteins (Santos et al, 1988). Whether the vesicular structures present in pex23 strains represent precursors to mature peroxisomes or are simply small peroxisomes lacking their full complement of peroxisomal proteins is unknown at present.…”

Section: Tw Brown Et Almentioning

confidence: 99%

“…Sequences involved in the sorting of peroxisomal membrane proteins have been identified for a few proteins and, in general, appear to be defined as a stretch of basic amino acid residues (McCammon et al, 1994;Dyer et al, 1996;Wiemer et al, 1996). The machinery for targeting proteins to the peroxisomal membrane is apparently different from that involved in the import of matrix proteins, because although most pex mutants are compromised in the import of matrix proteins, they do target peroxisomal membrane proteins and possess peroxisomal structures called "ghosts" that contain peroxisomal membrane proteins (Santos et al, 1988;Subramani, 1993Subramani, , 1998. Recently, cells from a Zellweger syndrome patient with a mutation in the PEX16 gene coding for a peroxin integral to the peroxisomal membrane were shown to be unable to import peroxisomal membrane proteins, implicating Pex16p in this process (South and Gould, 1999).…”

Section: Introductionmentioning

confidence: 99%

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Mutants of theYarrowia lipolytica PEX23Gene Encoding an Integral Peroxisomal Membrane Peroxin Mislocalize Matrix Proteins and Accumulate Vesicles Containing Peroxisomal Matrix and Membrane Proteins

Brown

Titorenko

Rachubinski

2000

MBoC

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pex mutants are defective in peroxisome assembly. The mutant strain pex23-1 of the yeast Yarrowia lipolytica lacks morphologically recognizable peroxisomes and mislocalizes all peroxisomal matrix proteins investigated preferentially to the cytosol. pex23 strains accumulate vesicular structures containing both peroxisomal matrix and membrane proteins. The PEX23 gene was isolated by functional complementation of the pex23-1 strain and encodes a protein, Pex23p, of 418 amino acids (47,588 Da). Pex23p exhibits high sequence similarity to two hypothetical proteins of the yeastSaccharomyces cerevisiae. Pex23p is an integral membrane protein of peroxisomes that is completely, or nearly completely, sequestered from the cytosol. Pex23p is detected at low levels in cells grown in medium containing glucose, and its levels are significantly increased by growth in medium containing oleic acid, the metabolism of which requires intact peroxisomes.

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Section: Tw Brown Et Almentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Mutants of theYarrowia lipolytica PEX23Gene Encoding an Integral Peroxisomal Membrane Peroxin Mislocalize Matrix Proteins and Accumulate Vesicles Containing Peroxisomal Matrix and Membrane Proteins

Brown

Titorenko

Rachubinski

2000

MBoC

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confidence: 99%

“…The sorting of peroxisomal membrane proteins is much less well understood than the sorting of matrix proteins, although it appears that the two pathways are independent. Although most pex mutants fail to target proteins to the peroxisomal matrix, mislocalizing them to the cytosol, they do target peroxisomal membrane proteins to vestigial structures called "peroxisome ghosts" (Santos et al, 1988; Subramani, 1993Subramani, , 1998.The peroxin Pex19p has been isolated from a variety of organisms, including humans and Chinese hamster and the yeasts Saccharomyces cerevisiae and Pichia pastoris (Braun et al, 1994;James et al, 1994; Gö tte et al, 1998;Matsuzono et al 1999;Snyder et al, 1999a). Pex19p has been shown to be primarily a cytosolic protein that can interact with a number of peroxisomal membrane proteins (Gö tte et al, 1998;Snyder et al, 1999aSnyder et al, , 1999bSnyder et al, , 2000Hettema et al, 2000;Sacksteder et al, 2000).…”

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confidence: 99%

Yarrowia lipolyticaCells Mutant for the Peroxisomal Peroxin Pex19p Contain Structures Resembling Wild-Type Peroxisomes

Lambkin

Rachubinski

2001

MBoC

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PEX genes encode peroxins, which are proteins required for peroxisome assembly. The PEX19 gene of the yeast Yarrowia lipolytica was isolated by functional complementation of the oleic acid-nonutilizing strain pex19-1 and encodes Pex19p, a protein of 324 amino acids (34,822 Da). Subcellular fractionation and immunofluorescence microscopy showed Pex19p to be localized primarily to peroxisomes. Pex19p is detected in cells grown in glucose-containing medium, and its levels are not increased by incubation of cells in oleic acid-containing medium, the metabolism of which requires intact peroxisomes. pex19 cells preferentially mislocalize peroxisomal matrix proteins and the peripheral intraperoxisomal membrane peroxin Pex16p to the cytosol, although small amounts of these proteins could be reproducibly localized to a subcellular fraction enriched for peroxisomes. In contrast, the peroxisomal integral membrane protein Pex2p exhibits greatly reduced levels in pex19 cells compared with its levels in wild-type cells. Importantly, pex19 cells were shown by electron microscopy to contain structures that resemble wild-type peroxisomes in regards to size, shape, number, and electron density. Subcellular fractionation and isopycnic density gradient centrifugation confirmed the presence of vesicular structures in pex19 mutant strains that were similar in density to wild-type peroxisomes and that contained profiles of peroxisomal matrix and membrane proteins that are similar to, yet distinct from, those of wild-type peroxisomes. Because peroxisomal structures form in pex19 cells, Pex19p apparently does not function as a peroxisomal membrane protein receptor in Y. lipolytica. Our results are consistent with a role for Y. lipolytica Pex19p in stabilizing the peroxisomal membrane. INTRODUCTIONPeroxisomes, together with the glyoxysomes of plants and the glycosomes of trypanosomes, make up the microbody family of organelles (de Duve, 1996). In electron micrographs, peroxisomes appear spherical in shape, surrounded by a single unit membrane and containing a granular matrix and sometimes a paracrystalline core. The functions of peroxisomes vary depending on the organism, cell type, and physiological conditions. Functions that have been conserved from yeast to humans include the ␤-oxidation of fatty acids and the decomposition of hydrogen peroxide by catalase (for reviews, see Lazarow and Fujiki, 1985;van den Bosch et al., 1992). Proteins that are required for the proper functioning and biogenesis of peroxisomes have collectively been termed peroxins .The importance of peroxisomes for human growth and development is underscored by a group of genetic disorders known as the peroxisome biogenesis disorders (PBD), including Zellweger syndrome, rhizomelic chondrodysplasia punctata, and neonatal adrenoleukodystrophy, in which peroxisomes fail to assemble normally (for reviews, see Lazarow and Moser, 1994;Fujiki, 1997Fujiki, , 2000. A great deal of attention has been paid recently to defining the molecular bases of these diseases, in particular...

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“…Several mutations affecting this biogenic mechanism in animals have been described (Wanders, 2004). In humans, these mutations can produce severe (often lethal) diseases such as the Zellweger Syndrome (Santos et al, 1988), the prototype of the group of peroxisome biogenesis disorders (PBDs) (Oglesbee, 2005). The gene defects have been elucidated for the majority of PBDs (Gould and Valle, 2000;Wanders, 2004).…”

Section: Introductionmentioning

confidence: 99%

Evaluation of the role of the Endoplasmic Reticulum-Golgi transit in the biogenesis of peroxisomal membrane proteins in wild type and peroxisome biogenesis mutant CHO cells

Toro¹,

Arredondo²,

Córdova³

et al. 2007

Biol. Res.

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Peroxisomes are thought to be formed by division of pre-existing peroxisomes after the import of newly synthesized proteins. However, it has been recently suggested that the endoplasmic reticulum (ER) provides an alternative de novo mechanism for peroxisome biogenesis in some cells. To test a possible role of the ERGolgi transit in peroxisome biogenesis in mammalian cells, we evaluated the biogenesis of three peroxisomal membrane proteins (PMPs): ALDRP (adrenoleukodystrophy related protein), PMP70 and Pex3p in CHO cells. We constructed chimeric genes encoding these PMPs and green fluorescent protein (GFP), and transiently transfected them to wild type and mutant CHO cells, in which normal peroxisomes were replaced by peroxisomal membrane ghosts. The expressed proteins were targeted to peroxisomes and peroxisomal ghosts correctly in the presence or absence of Brefeldin A (BFA), a drug known to block the ER-Golgi transit. Furthermore, low temperature did not disturb the targeting of Pex3p-GFP to peroxisomes. We also constructed two chimeric proteins of PMPs containing an ER retention signal "DEKKMP": GFP-ALDRP-DEKKMP and myc-Pex3p-DEKKMP. These proteins were mostly targeted to peroxisomes. No colocalization with an ER maker was found. These results suggest that the classical ER-Golgi pathway does not play a major role in the biogenesis of mammalian PMPs.

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Peroxisomal Membrane Ghosts in Zellweger Syndrome—Aberrant Organelle Assembly

Cited by 318 publications

References 28 publications

Mutants of theYarrowia lipolytica PEX23Gene Encoding an Integral Peroxisomal Membrane Peroxin Mislocalize Matrix Proteins and Accumulate Vesicles Containing Peroxisomal Matrix and Membrane Proteins

Mutants of theYarrowia lipolytica PEX23Gene Encoding an Integral Peroxisomal Membrane Peroxin Mislocalize Matrix Proteins and Accumulate Vesicles Containing Peroxisomal Matrix and Membrane Proteins

Yarrowia lipolyticaCells Mutant for the Peroxisomal Peroxin Pex19p Contain Structures Resembling Wild-Type Peroxisomes

Evaluation of the role of the Endoplasmic Reticulum-Golgi transit in the biogenesis of peroxisomal membrane proteins in wild type and peroxisome biogenesis mutant CHO cells

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