Artykuły w czasopismach na temat „Peroxisome”
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1
Bascom, Roger A., Honey Chan i Richard A. Rachubinski. "Peroxisome Biogenesis Occurs in an Unsynchronized Manner in Close Association with the Endoplasmic Reticulum in Temperature-sensitiveYarrowia lipolyticaPex3p Mutants". Molecular Biology of the Cell 14, nr 3 (marzec 2003): 939–57. http://dx.doi.org/10.1091/mbc.e02-10-0633.
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Pex3p is a peroxisomal integral membrane protein required early in peroxisome biogenesis, and Pex3p-deficient cells lack identifiable peroxisomes. Two temperature-sensitive pex3 mutant strains of the yeast Yarrowia lipolytica were made to investigate the role of Pex3p in the early stages of peroxisome biogenesis. In glucose medium at 16°C, these mutants underwent de novo peroxisome biogenesis and exhibited early matrix protein sequestration into peroxisome-like structures found at the endoplasmic reticulum-rich periphery of cells or sometimes associated with nuclei. The de novo peroxisome biogenesis seemed unsynchronized, with peroxisomes occurring at different stages of development both within cells and between cells. Cells with peripheral nascent peroxisomes and cells with structures morphologically distinct from peroxisomes, such as semi/circular tubular structures that immunostained with antibodies to peroxisomal matrix proteins and to the endoplasmic reticulum-resident protein Kar2p, and that surrounded lipid droplets, were observed during up-regulation of peroxisome biogenesis in cells incubated in oleic acid medium at 16°C. These structures were not detected in wild-type or Pex3p-deficient cells. Their role in peroxisome biogenesis remains unclear. Targeting of peroxisomal matrix proteins to these structures suggests that Pex3p directly or indirectly sequesters components of the peroxisome biogenesis machinery. Such a role is consistent with Pex3p overexpression producing cells with fewer, larger, and clustered peroxisomes.
2
Heyman, J. A., E. Monosov i S. Subramani. "Role of the PAS1 gene of Pichia pastoris in peroxisome biogenesis." Journal of Cell Biology 127, nr 5 (1.12.1994): 1259–73. http://dx.doi.org/10.1083/jcb.127.5.1259.
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Several groups have reported the cloning and sequencing of genes involved in the biogenesis of yeast peroxisomes. Yeast strains bearing mutations in these genes are unable to grow on carbon sources whose metabolism requires peroxisomes, and these strains lack morphologically normal peroxisomes. We report the cloning of Pichia pastoris PAS1, the homologue (based on a high level of protein sequence similarity) of the Saccharomyces cerevisiae PAS1. We also describe the creation and characterization of P. pastoris pas1 strains. Electron microscopy on the P. pastoris pas1 cells revealed that they lack morphologically normal peroxisomes, and instead contain membrane-bound structures that appear to be small, mutant peroxisomes, or "peroxisome ghosts." These "ghosts" proliferated in response to induction on peroxisome-requiring carbon sources (oleic acid and methanol), and they were distributed to daughter cells. Biochemical analysis of cell lysates revealed that peroxisomal proteins are induced normally in pas1 cells. Peroxisome ghosts from pas1 cells were purified on sucrose gradients, and biochemical analysis showed that these ghosts, while lacking several peroxisomal proteins, did import varying amounts of several other peroxisomal proteins. The existence of detectable peroxisome ghosts in P. pastoris pas1 cells, and their ability to import some proteins, stands in contrast with the results reported by Erdmann et al. (1991) for the S. cerevisiae pas1 mutant, in which they were unable to detect peroxisome-like structures. We discuss the role of PAS1 in peroxisome biogenesis in light of the new information regarding peroxisome ghosts in pas1 cells.
3
Chang, Jinlan, Fred D. Mast, Andrei Fagarasanu, Dorian A. Rachubinski, Gary A. Eitzen, Joel B. Dacks i Richard A. Rachubinski. "Pex3 peroxisome biogenesis proteins function in peroxisome inheritance as class V myosin receptors". Journal of Cell Biology 187, nr 2 (12.10.2009): 233–46. http://dx.doi.org/10.1083/jcb.200902117.
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In Saccharomyces cerevisiae, peroxisomal inheritance from mother cell to bud is conducted by the class V myosin motor, Myo2p. However, homologues of S. cerevisiae Myo2p peroxisomal receptor, Inp2p, are not readily identifiable outside the Saccharomycetaceae family. Here, we demonstrate an unexpected role for Pex3 proteins in peroxisome inheritance. Both Pex3p and Pex3Bp are peroxisomal integral membrane proteins that function as peroxisomal receptors for class V myosin through direct interaction with the myosin globular tail. In cells lacking Pex3Bp, peroxisomes are preferentially retained by the mother cell, whereas most peroxisomes gather and are transferred en masse to the bud in cells overexpressing Pex3Bp or Pex3p. Our results reveal an unprecedented role for members of the Pex3 protein family in peroxisome motility and inheritance in addition to their well-established role in peroxisome biogenesis at the endoplasmic reticulum. Our results point to a temporal link between peroxisome formation and inheritance and delineate a general mechanism of peroxisome inheritance in eukaryotic cells.
4
Zhang, J. W., Y. Han i P. B. Lazarow. "Novel peroxisome clustering mutants and peroxisome biogenesis mutants of Saccharomyces cerevisiae." Journal of Cell Biology 123, nr 5 (1.12.1993): 1133–47. http://dx.doi.org/10.1083/jcb.123.5.1133.
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The goal of this research is to identify and characterize the protein machinery that functions in the intracellular translocation and assembly of peroxisomal proteins in Saccharomyces cerevisiae. Several genes encoding proteins that are essential for this process have been identified previously by Kunau and collaborators, but the mutant collection was incomplete. We have devised a positive selection procedure that identifies new mutants lacking peroxisomes or peroxisomal function. Immunofluorescence procedures for yeast were simplified so that these mutants could be rapidly and efficiently screened for those in which peroxisome biogenesis is impaired. With these tools, we have identified four complementation groups of peroxisome biogenesis mutants, and one group that appears to express reduced amounts of peroxisomal proteins. Two of our mutants lack recognizable peroxisomes, although they might contain peroxisomal membrane ghosts like those found in Zellweger syndrome. Two are selectively defective in packaging peroxisomal proteins and moreover show striking intracellular clustering of the peroxisomes. The distribution of mutants among complementation groups implies that the collection of peroxisome biogenesis mutants is still incomplete. With the procedures described, it should prove straightforward to isolate mutants from additional complementation groups.
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Somborac, Tamara, Güleycan Lutfullahoglu Bal, Kaneez Fatima, Helena Vihinen, Anja Paatero, Eija Jokitalo, Ville O. Paavilainen i Svetlana Konovalova. "The subset of peroxisomal tail-anchored proteins do not reach peroxisomes via ER, instead mitochondria can be involved". PLOS ONE 18, nr 12 (1.12.2023): e0295047. http://dx.doi.org/10.1371/journal.pone.0295047.
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Peroxisomes are membrane-enclosed organelles with important roles in fatty acid breakdown, bile acid synthesis and biosynthesis of sterols and ether lipids. Defects in peroxisomes result in severe genetic diseases, such as Zellweger syndrome and neonatal adrenoleukodystrophy. However, many aspects of peroxisomal biogenesis are not well understood. Here we investigated delivery of tail-anchored (TA) proteins to peroxisomes in mammalian cells. Using glycosylation assays we showed that peroxisomal TA proteins do not enter the endoplasmic reticulum (ER) in both wild type (WT) and peroxisome-lacking cells. We observed that in cells lacking the essential peroxisome biogenesis factor, PEX19, peroxisomal TA proteins localize mainly to mitochondria. Finally, to investigate peroxisomal TA protein targeting in cells with fully functional peroxisomes we used a proximity biotinylation approach. We showed that while ER-targeted TA construct was exclusively inserted into the ER, peroxisome-targeted TA construct was inserted to both peroxisomes and mitochondria. Thus, in contrast to previous studies, our data suggest that some peroxisomal TA proteins do not insert to the ER prior to their delivery to peroxisomes, instead, mitochondria can be involved.
6
Kim, Jung-Ae. "Peroxisome Metabolism in Cancer". Cells 9, nr 7 (14.07.2020): 1692. http://dx.doi.org/10.3390/cells9071692.
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Peroxisomes are metabolic organelles involved in lipid metabolism and cellular redoxbalance. Peroxisomal function is central to fatty acid oxidation, ether phospholipid synthesis, bile acidsynthesis, and reactive oxygen species homeostasis. Human disorders caused by genetic mutations inperoxisome genes have led to extensive studies on peroxisome biology. Peroxisomal defects are linkedto metabolic dysregulation in diverse human diseases, such as neurodegeneration and age-relateddisorders, revealing the significance of peroxisome metabolism in human health. Cancer is a diseasewith metabolic aberrations. Despite the critical role of peroxisomes in cell metabolism, the functionaleects of peroxisomes in cancer are not as well recognized as those of other metabolic organelles,such as mitochondria. In addition, the significance of peroxisomes in cancer is less appreciated thanit is in degenerative diseases. In this review, I summarize the metabolic pathways in peroxisomesand the dysregulation of peroxisome metabolism in cancer. In addition, I discuss the potential ofinactivating peroxisomes to target cancer metabolism, which may pave the way for more eectivecancer treatment.
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Voorn-Brouwer, Tineke, Astrid Kragt, Henk F. Tabak i Ben Distel. "Peroxisomal membrane proteins are properly targeted to peroxisomes in the absence of COPI- and COPII-mediated vesicular transport". Journal of Cell Science 114, nr 11 (1.06.2001): 2199–204. http://dx.doi.org/10.1242/jcs.114.11.2199.
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The classic model for peroxisome biogenesis states that new peroxisomes arise by the fission of pre-existing ones and that peroxisomal matrix and membrane proteins are recruited directly from the cytosol. Recent studies challenge this model and suggest that some peroxisomal membrane proteins might traffic via the endoplasmic reticulum to peroxisomes. We have studied the trafficking in human fibroblasts of three peroxisomal membrane proteins, Pex2p, Pex3p and Pex16p, all of which have been suggested to transit the endoplasmic reticulum before arriving in peroxisomes. Here, we show that targeting of these peroxisomal membrane proteins is not affected by inhibitors of COPI and COPII that block vesicle transport in the early secretory pathway. Moreover, we have obtained no evidence for the presence of these peroxisomal membrane proteins in compartments other than peroxisomes and demonstrate that COPI and COPII inhibitors do not affect peroxisome morphology or integrity. Together, these data fail to provide any evidence for a role of the endoplasmic reticulum in peroxisome biogenesis.
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Munck, Joanne M., Alison M. Motley, James M. Nuttall i Ewald H. Hettema. "A dual function for Pex3p in peroxisome formation and inheritance". Journal of Cell Biology 187, nr 4 (9.11.2009): 463–71. http://dx.doi.org/10.1083/jcb.200906161.
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Saccharomyces cerevisiae Pex3p has been shown to act at the ER during de novo peroxisome formation. However, its steady state is at the peroxisomal membrane, where its role is debated. Here we show that Pex3p has a dual function: one in peroxisome formation and one in peroxisome segregation. We show that the peroxisome retention factor Inp1p interacts physically with Pex3p in vitro and in vivo, and split-GFP analysis shows that the site of interaction is the peroxisomal membrane. Furthermore, we have generated PEX3 alleles that support peroxisome formation but fail to support recruitment of Inp1p to peroxisomes, and as a consequence are affected in peroxisome segregation. We conclude that Pex3p functions as an anchor for Inp1p at the peroxisomal membrane, and that this function is independent of its role at the ER in peroxisome biogenesis.
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Singin, Öznur, Artur Astapenka, Victor Costina, Sandra Kühl, Nina Bonekamp, Oliver Drews i Markus Islinger. "Analysis of the Mouse Hepatic Peroxisome Proteome—Identification of Novel Protein Constituents Using a Semi-Quantitative SWATH-MS Approach". Cells 13, nr 2 (17.01.2024): 176. http://dx.doi.org/10.3390/cells13020176.
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Ongoing technical and bioinformatics improvements in mass spectrometry (MS) allow for the identifying and quantifying of the enrichment of increasingly less-abundant proteins in individual fractions. Accordingly, this study reassessed the proteome of mouse liver peroxisomes by the parallel isolation of peroxisomes from a mitochondria- and a microsome-enriched prefraction, combining density-gradient centrifugation with a semi-quantitative SWATH-MS proteomics approach to unveil novel peroxisomal or peroxisome-associated proteins. In total, 1071 proteins were identified using MS and assessed in terms of their distribution in either high-density peroxisomal or low-density gradient fractions, containing the bulk of organelle material. Combining the data from both fractionation approaches allowed for the identification of specific protein profiles characteristic of mitochondria, the ER and peroxisomes. Among the proteins significantly enriched in the peroxisomal cluster were several novel peroxisomal candidates. Five of those were validated by colocalization in peroxisomes, using confocal microscopy. The peroxisomal import of HTATIP2 and PAFAH2, which contain a peroxisome-targeting sequence 1 (PTS1), could be confirmed by overexpression in HepG2 cells. The candidates SAR1B and PDCD6, which are known ER-exit-site proteins, did not directly colocalize with peroxisomes, but resided at ER sites, which frequently surrounded peroxisomes. Hence, both proteins might concentrate at presumably co-purified peroxisome-ER membrane contacts. Intriguingly, the fifth candidate, OCIA domain-containing protein 1, was previously described as decreasing mitochondrial network formation. In this work, we confirmed its peroxisomal localization and further observed a reduction in peroxisome numbers in response to OCIAD1 overexpression. Hence, OCIAD1 appears to be a novel protein, which has an impact on both mitochondrial and peroxisomal maintenance.
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Rapp, S., R. Saffrich, M. Anton, U. Jakle, W. Ansorge, K. Gorgas i W. W. Just. "Microtubule-based peroxisome movement". Journal of Cell Science 109, nr 4 (1.04.1996): 837–49. http://dx.doi.org/10.1242/jcs.109.4.837.
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The association of peroxisomes with cytoskeletal structures was investigated both by electron microscopy and by kinetic analysis of peroxisome movement. The morphological studies indicated distinct interactions of peroxisomes with microtubules and frequently revealed multiple contact sites. The kinetic approach utilised microinjection and import of fluorescein-labeled luciferase in order to mark and track peroxisomes in vivo. Peroxisomal motility was analysed by time-lapse imaging and fluorescence microscopy. According to their movement peroxisomes were classified into two groups. Group 1 peroxisomes comprising the majority of organelles at 37 degrees C moved slowly with an average velocity of 0.024 +/- 0.012 micron/second whereas the movement of group 2 peroxisomes, 10–15% of the total population, was saltatory exhibiting an average velocity of 0.26 +/- 0.17 micron/second with maximal values of more than 2 microns/second. Saltations were completely abolished by the microtubule-depolymerising drug nocodazole and were slightly reduced by about 25% by cytochalasin D which disrupts the actin microfilament system. Double fluorescence labeling of both peroxisomes and microtubules revealed peroxisome saltations linked to distinct microtubule tracks. Cellular depletion of endogenous levels of NTPs as well as the use of 5′-adenylylimidodiphosphate, a nonhydrolysable ATP analog, applied to a permeabilised cell preparation both completely blocked peroxisomal movement. These data suggest an ATPase dependent, microtubule-based mechanism of peroxisome movement. Both the intact and the permeabilised cell system presented in this paper for the first time allow kinetic measurements on peroxisomal motility and thus will be extremely helpful in the biochemical characterisation of the motor proteins involved.
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Shimozawa, Nobuyuki, Tomoko Nagase, Yasuhiko Takemoto, Michinori Funato, Naomi Kondo i Yasuyuki Suzuki. "Topical Review: Molecular and Neurologic Findings of Peroxisome Biogenesis Disorders". Journal of Child Neurology 19, nr 3 (marzec 2004): 326–29. http://dx.doi.org/10.1177/08830738040190031001.
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Peroxisomal disorders, an expanding group of genetic disorders in humans, can be grouped into three categories: peroxisome biogenesis disorders, single peroxisomal enzyme deficiencies, and contiguous gene syndrome. At present, 13 complementation groups of peroxisome biogenesis disorders and their responsible genes have been identified, including our newly identified group with a PEX14 defect. We describe neuronal abnormalities related to deficiencies in peroxisomes and the phenotype-genotype relationship in peroxisome biogenesis disorders. We also identified 32 Japanese patients with peroxisome biogenesis disorders, subdivided into six complementation groups. Our institution acts as the only diagnostic center for studies on peroxisomal disorders in Japan. ( J Child Neurol 2005;20:326—329).
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South, Sarah T., i Stephen J. Gould. "Peroxisome Synthesis in the Absence of Preexisting Peroxisomes". Journal of Cell Biology 144, nr 2 (25.01.1999): 255–66. http://dx.doi.org/10.1083/jcb.144.2.255.
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Zellweger syndrome and related diseases are caused by defective import of peroxisomal matrix proteins. In all previously reported Zellweger syndrome cell lines the defect could be assigned to the matrix protein import pathway since peroxisome membranes were present, and import of integral peroxisomal membrane proteins was normal. However, we report here a Zellweger syndrome patient (PBD061) with an unusual cellular phenotype, an inability to import peroxisomal membrane proteins. We also identified human PEX16, a novel integral peroxisomal membrane protein, and found that PBD061 had inactivating mutations in the PEX16 gene. Previous studies have suggested that peroxisomes arise from preexisting peroxisomes but we find that expression of PEX16 restores the formation of new peroxisomes in PBD061 cells. Peroxisome synthesis and peroxisomal membrane protein import could be detected within 2–3 h of PEX16 injection and was followed by matrix protein import. These results demonstrate that peroxisomes do not necessarily arise from division of preexisting peroxisomes. We propose that peroxisomes may form by either of two pathways: one that involves PEX11-mediated division of preexisting peroxisomes, and another that involves PEX16-mediated formation of peroxisomes in the absence of preexisting peroxisomes.
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Smith, Jennifer J., Marcello Marelli, Rowan H. Christmas, Franco J. Vizeacoumar, David J. Dilworth, Trey Ideker, Timothy Galitski, Krassen Dimitrov, Richard A. Rachubinski i John D. Aitchison. "Transcriptome profiling to identify genes involved in peroxisome assembly and function". Journal of Cell Biology 158, nr 2 (22.07.2002): 259–71. http://dx.doi.org/10.1083/jcb.200204059.
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Yeast cells were induced to proliferate peroxisomes, and microarray transcriptional profiling was used to identify PEX genes encoding peroxins involved in peroxisome assembly and genes involved in peroxisome function. Clustering algorithms identified 224 genes with expression profiles similar to those of genes encoding peroxisomal proteins and genes involved in peroxisome biogenesis. Several previously uncharacterized genes were identified, two of which, YPL112c and YOR084w, encode proteins of the peroxisomal membrane and matrix, respectively. Ypl112p, renamed Pex25p, is a novel peroxin required for the regulation of peroxisome size and maintenance. These studies demonstrate the utility of comparative gene profiling as an alternative to functional assays to identify genes with roles in peroxisome biogenesis.
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Dodt, G., i S. J. Gould. "Multiple PEX genes are required for proper subcellular distribution and stability of Pex5p, the PTS1 receptor: evidence that PTS1 protein import is mediated by a cycling receptor." Journal of Cell Biology 135, nr 6 (15.12.1996): 1763–74. http://dx.doi.org/10.1083/jcb.135.6.1763.
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PEX5 encodes the type-1 peroxisomal targeting signal (PTS1) receptor, one of at least 15 peroxins required for peroxisome biogenesis. Pex5p has a bimodal distribution within the cell, mostly cytosolic with a small amount bound to peroxisomes. This distribution indicates that Pex5p may function as a cycling receptor, a mode of action likely to require interaction with additional peroxins. Loss of peroxins required for protein translocation into the peroxisome (PEX2 or PEX12) resulted in accumulation of Pex5p at docking sites on the peroxisome surface. Pex5p also accumulated on peroxisomes in normal cells under conditions which inhibit protein translocation into peroxisomes (low temperature or ATP depletion), returned to the cytoplasm when translocation was restored, and reaccumulated on peroxisomes when translocation was again inhibited. Translocation inhibiting conditions did not result in Pex5p redistribution in cells that lack detectable peroxisomes. Thus, it appears that Pex5p can cycle repeatedly between the cytoplasm and peroxisome. Altered activity of the peroxin defective in CG7 cells leads to accumulation of Pex5p within the peroxisome, indicating that Pex5p may actually enter the peroxisome lumen at one point in its cycle. In addition, we found that the PTS1 receptor was extremely unstable in the peroxin-deficient CG1, CG4, and CG8 cells. Altered distribution or stability of the PTS1 receptor in all cells with a defect in PTS1 protein import implies that the genes mutated in these cell lines encode proteins with a direct role in peroxisomal protein import.
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Marelli, Marcello, Jennifer J. Smith, Sunhee Jung, Eugene Yi, Alexey I. Nesvizhskii, Rowan H. Christmas, Ramsey A. Saleem i in. "Quantitative mass spectrometry reveals a role for the GTPase Rho1p in actin organization on the peroxisome membrane". Journal of Cell Biology 167, nr 6 (13.12.2004): 1099–112. http://dx.doi.org/10.1083/jcb.200404119.
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We have combined classical subcellular fractionation with large-scale quantitative mass spectrometry to identify proteins that enrich specifically with peroxisomes of Saccharomyces cerevisiae. In two complementary experiments, isotope-coded affinity tags and tandem mass spectrometry were used to quantify the relative enrichment of proteins during the purification of peroxisomes. Mathematical modeling of the data from 306 quantified proteins led to a prioritized list of 70 candidates whose enrichment scores indicated a high likelihood of them being peroxisomal. Among these proteins, eight novel peroxisome-associated proteins were identified. The top novel peroxisomal candidate was the small GTPase Rho1p. Although Rho1p has been shown to be tethered to membranes of the secretory pathway, we show that it is specifically recruited to peroxisomes upon their induction in a process dependent on its interaction with the peroxisome membrane protein Pex25p. Rho1p regulates the assembly state of actin on the peroxisome membrane, thereby controlling peroxisome membrane dynamics and biogenesis.
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Hosoi, Ken-ichiro, Non Miyata, Satoru Mukai, Satomi Furuki, Kanji Okumoto, Emily H. Cheng i Yukio Fujiki. "The VDAC2–BAK axis regulates peroxisomal membrane permeability". Journal of Cell Biology 216, nr 3 (7.02.2017): 709–22. http://dx.doi.org/10.1083/jcb.201605002.
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Peroxisomal biogenesis disorders (PBDs) are fatal genetic diseases consisting of 14 complementation groups (CGs). We previously isolated a peroxisome-deficient Chinese hamster ovary cell mutant, ZP114, which belongs to none of these CGs. Using a functional screening strategy, VDAC2 was identified as rescuing the peroxisomal deficiency of ZP114 where VDAC2 expression was not detected. Interestingly, knockdown of BAK or overexpression of the BAK inhibitors BCL-XL and MCL-1 restored peroxisomal biogenesis in ZP114 cells. Although VDAC2 is not localized to the peroxisome, loss of VDAC2 shifts the localization of BAK from mitochondria to peroxisomes, resulting in peroxisomal deficiency. Introduction of peroxisome-targeted BAK harboring the Pex26p transmembrane region into wild-type cells resulted in the release of peroxisomal matrix proteins to cytosol. Moreover, overexpression of BAK activators PUMA and BIM permeabilized peroxisomes in a BAK-dependent manner. Collectively, these findings suggest that BAK plays a role in peroxisomal permeability, similar to mitochondrial outer membrane permeabilization.
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Perry, Ryan J., Fred D. Mast i Richard A. Rachubinski. "Endoplasmic Reticulum-Associated Secretory Proteins Sec20p, Sec39p, and Dsl1p Are Involved in Peroxisome Biogenesis". Eukaryotic Cell 8, nr 6 (3.04.2009): 830–43. http://dx.doi.org/10.1128/ec.00024-09.
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ABSTRACT Two pathways have been identified for peroxisome formation: (i) growth and division and (ii) de novo synthesis. Recent experiments determined that peroxisomes originate at the endoplasmic reticulum (ER). Although many proteins have been implicated in the peroxisome biogenic program, no proteins in the eukaryotic secretory pathway have been identified as having roles in peroxisome formation. Using the yeast Saccharomyces cerevisiae regulatable Tet promoter Hughes clone collection, we found that repression of the ER-associated secretory proteins Sec20p and Sec39p resulted in mislocalization of the peroxisomal matrix protein chimera Pot1p-green fluorescent protein (GFP) to the cytosol. Likewise, the peroxisomal membrane protein chimera Pex3p-GFP localized to tubular-vesicular structures in cells suppressed for Sec20p, Sec39p, and Dsl1p, which form a complex at the ER. Loss of Sec39p attenuated formation of Pex3p-derived peroxisomal structures following galactose induction of Pex3p-GFP expression from the GAL1 promoter. Expression of Sec20p, Sec39p, and Dsl1p was moderately increased in yeast grown under conditions that proliferate peroxisomes, and Sec20p, Sec39p, and Dsl1p were found to cofractionate with peroxisomes and colocalize with Pex3p-monomeric red fluorescent protein under these conditions. Our results show that SEC20, SEC39, and DSL1 are essential secretory genes involved in the early stages of peroxisome assembly, and this work is the first to identify and characterize an ER-associated secretory machinery involved in peroxisome biogenesis.
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Elgersma, Y., M. van den Berg, H. F. Tabak i B. Distel. "An efficient positive selection procedure for the isolation of peroxisomal import and peroxisome assembly mutants of Saccharomyces cerevisiae." Genetics 135, nr 3 (1.11.1993): 731–40. http://dx.doi.org/10.1093/genetics/135.3.731.
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Abstract To study peroxisome biogenesis, we developed a procedure to select for Saccharomyces cerevisiae mutants defective in peroxisomal protein import or peroxisome assembly. For this purpose, a chimeric gene was constructed encoding the bleomycin resistance protein linked to the peroxisomal protein luciferase. In wild-type cells this chimeric protein is imported into the peroxisome, which prevents the neutralizing interaction of the chimeric protein with its toxic phleomycin ligand. Peroxisomal import and peroxisome assembly mutants are unable to import this chimeric protein into their peroxisomes. This enables the bleomycin moiety of the chimeric protein to bind phleomycin, thereby preventing its toxicity. The selection is very efficient: upon mutagenesis, 84 (10%) of 800 phleomycin resistant colonies tested were unable to grow on oleic acid. This rate could be increased to 25% using more stringent selection conditions. The selection procedure is very specific; all oleic acid non utilizing (onu) mutants tested were disturbed in peroxisomal import and/or peroxisome assembly. The pas (peroxisome assembly) mutants that have been used for complementation analysis represent 12 complementation groups including three novel ones, designated pas20, pas21 and pas22.
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Wei, Xiaofan, Yunash Maharjan, Debra Dorotea, Raghbendra-Kumar Dutta, Donghyun Kim, Hyunsoo Kim, Yizhu Mu, Channy Park i Raekil Park. "Knockdown of PEX16 Induces Autophagic Degradation of Peroxisomes". International Journal of Molecular Sciences 22, nr 15 (26.07.2021): 7989. http://dx.doi.org/10.3390/ijms22157989.
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Peroxisome abundance is regulated by homeostasis between the peroxisomal biogenesis and degradation processes. Peroxin 16 (PEX16) is a peroxisomal protein involved in trafficking membrane proteins for de novo peroxisome biogenesis. The present study demonstrates that PEX16 also modulates peroxisome abundance through pexophagic degradation. PEX16 knockdown in human retinal pigment epithelial-1 cells decreased peroxisome abundance and function, represented by reductions in the expression of peroxisome membrane protein ABCD3 and the levels of cholesterol and plasmalogens, respectively. The activation of pexophagy under PEX16 knockdown was shown by (i) abrogated peroxisome loss under PEX16 knockdown in autophagy-deficient ATG5 knockout cell lines, and (ii) increased autophagy flux and co-localization of p62—an autophagy adaptor protein—with ABCD3 in the presence of the autophagy inhibitor chloroquine. However, the levels of cholesterol and plasmalogens did not recover despite the restoration of peroxisome abundance following chloroquine treatment. Thus, PEX16 is indispensable for maintaining peroxisome homeostasis by regulating not only the commonly known biogenesis pathway but also the autophagic degradation of peroxisomes.
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Breitling, Rainer, Orzala Sharif, Michelle L. Hartman i Skaidrite K. Krisans. "Loss of Compartmentalization Causes Misregulation of Lysine Biosynthesis in Peroxisome-Deficient Yeast Cells". Eukaryotic Cell 1, nr 6 (grudzień 2002): 978–86. http://dx.doi.org/10.1128/ec.1.6.978-986.2002.
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ABSTRACT To characterize the metabolic role of peroxisomes in yeast cells under physiological conditions, we performed a comprehensive meta-analysis of published microarray data. Previous studies of yeast peroxisomes have mainly been focused on the function of peroxisomes under extreme conditions, such as growth on oleate or methanol as the sole carbon source, and may therefore not be representative of the normal physiological role of yeast peroxisomes. Surprisingly, our analysis of the microarray data reveals that the only pathway responding to peroxisome deficiency in mid-log phase is lysine biosynthesis, whereas classical peroxisomal pathways such as beta-oxidation are unaffected. We show that the upregulation of lysine biosynthesis genes in peroxisome-deficient yeasts shares many characteristics with the physiological response to lysine starvation. We provide data that suggest that this is the result of a “pathological” stimulation of the Lys14p transcriptional activator by the pathway intermediate aminoadipate semialdehyde. Mistargeting of the peroxisomal lysine pathway to the cytosol increases the active concentration of aminoadipate semialdehyde, which is no longer contained in the peroxisome and can now activate Lys14p at much lower levels than in wild-type yeasts. This is the first well-documented example of pathway misregulation in response to peroxisome deficiency and will be useful in understanding the phenotypic details of human peroxisome-deficient patients (Zellweger syndrome).
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Spong, A. P., i S. Subramani. "Cloning and characterization of PAS5: a gene required for peroxisome biogenesis in the methylotrophic yeast Pichia pastoris." Journal of Cell Biology 123, nr 3 (1.11.1993): 535–48. http://dx.doi.org/10.1083/jcb.123.3.535.
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The biogenesis and maintenance of cellular organelles is of fundamental importance in all eukaryotic cells. One such organelle is the peroxisome. The establishment of a genetic system to study peroxisome biogenesis in the methylotrophic yeast Pichia pastoris has yielded many different complementation groups of peroxisomal assembly (pas) or peroxisome-deficient (per) mutants. Each appears to be deficient in functional peroxisomes. One of these mutants, pas5, has been characterized, complemented, and the gene sequenced. Ultrastructural studies show that normal peroxisomes are not present in pas5, but aberrant peroxisomal structures resembling "membranous ghosts" are frequently observed. The "peroxisome ghosts" appear to be induced and segregated to daughter cells normally. Biochemical fractionation analysis of organelles of the pas5 mutant reveals that peroxisomal matrix enzymes are induced normally but are found mostly in the cytosol. However, purification of peroxisome ghosts from the mutant shows that small amounts (< 5%) of matrix enzymes are imported. The PAS5 gene was cloned and found to encode a 127-kD protein, which contains a 200-amino acid-long region of homology with PAS1, NEM-sensitive factor (NSF), and other related ATPases. Weak homology to a yeast myosin was also observed. The gene is not essential for growth on glucose but is essential for growth on oleic acid and methanol. The role of PAS5 in peroxisome biogenesis is discussed.
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Fujiki, Yukio, Non Miyata, Naomi Matsumoto i Shigehiko Tamura. "Dynamic and functional assembly of the AAA peroxins, Pex1p and Pex6p, and their membrane receptor Pex26p involved in shuttling of the PTS1 receptor Pex5p in peroxisome biogenesis". Biochemical Society Transactions 36, nr 1 (22.01.2008): 109–13. http://dx.doi.org/10.1042/bst0360109.
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The peroxisome is a single-membrane-bound organelle found in eukaryotes. The functional importance of peroxisomes in humans is highlighted by peroxisome-deficient PBDs (peroxisome biogenesis disorders), such as Zellweger syndrome. Two AAA (ATPase associated with various cellular activities) peroxins, Pex1p and Pex6p, are encoded by PEX1 and PEX6, the causal genes for CG (complementation group) 1 and CG4 PBDs respectively. PEX26, which is responsible for CG8 PBDs, codes for Pex26p, the recruiter of Pex1p–Pex6p complexes to peroxisomes. We recently assigned the binding regions between human Pex1p and Pex6p and elucidated the pivotal roles that the AAA cassettes, D1 and D2 domains, play in Pex1p–Pex6p interaction and in peroxisome biogenesis. ATP binding to both AAA cassettes of Pex1p and Pex6p was a prerequisite for the Pex1p–Pex6p interaction and peroxisomal localization, but ATP hydrolysis by the D2 domains was not required. Pex1p exists in two distinct oligomeric forms, a homo-oligomer in the cytosol and a hetero-oligomer on peroxisome membranes, with these possibly having distinct functions in peroxisome biogenesis. AAA peroxins are involved in the export from peroxisomes of Pex5p, the PTS1 (peroxisome-targeting signal type 1) receptor.
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Tam, Yuen Yi C., Juan C. Torres-Guzman, Franco J. Vizeacoumar, Jennifer J. Smith, Marcello Marelli, John D. Aitchison i Richard A. Rachubinski. "Pex11-related Proteins in Peroxisome Dynamics: A Role for the Novel Peroxin Pex27p in Controlling Peroxisome Size and Number in Saccharomyces cerevisiae". Molecular Biology of the Cell 14, nr 10 (październik 2003): 4089–102. http://dx.doi.org/10.1091/mbc.e03-03-0150.
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Transcriptome profiling identified the gene PEX25 encoding Pex25p, a peroxisomal membrane peroxin required for the regulation of peroxisome size and maintenance in Saccharomyces cerevisiae. Pex25p is related to a protein of unknown function encoded by the open reading frame, YOR193w, of the S. cerevisiae genome. Yor193p is a peripheral peroxisomal membrane protein that exhibits high sequence similarity not only to Pex25p but also to the peroxisomal membrane peroxin Pex11p. Unlike Pex25p and Pex11p, Yor193p is constitutively expressed in wild-type cells grown in oleic acid-containing medium, the metabolism of which requires intact peroxisomes. Cells deleted for the YOR193w gene show a few enlarged peroxisomes. Peroxisomes are greatly enlarged in cells harboring double deletions of the YOR193w and PEX25 genes, the YOR193w and PEX11 genes, and the PEX25 and PEX11 genes. Yeast two-hybrid analyses showed that Yor193p interacts with Pex25p and itself, Pex25p interacts with Yor193p and itself, and Pex11p interacts only with itself. Overexpression of YOR193w, PEX25, or PEX11 led to peroxisome proliferation and the formation of small peroxisomes. Our data suggest a role for Yor193p, renamed Pex27p, in controlling peroxisome size and number in S. cerevisiae.
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Chang, Chi-Lun, Aubrey V. Weigel, Maria S. Ioannou, H. Amalia Pasolli, C. Shan Xu, David R. Peale, Gleb Shtengel i in. "Spastin tethers lipid droplets to peroxisomes and directs fatty acid trafficking through ESCRT-III". Journal of Cell Biology 218, nr 8 (21.06.2019): 2583–99. http://dx.doi.org/10.1083/jcb.201902061.
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Lipid droplets (LDs) are neutral lipid storage organelles that transfer lipids to various organelles including peroxisomes. Here, we show that the hereditary spastic paraplegia protein M1 Spastin, a membrane-bound AAA ATPase found on LDs, coordinates fatty acid (FA) trafficking from LDs to peroxisomes through two interrelated mechanisms. First, M1 Spastin forms a tethering complex with peroxisomal ABCD1 to promote LD–peroxisome contact formation. Second, M1 Spastin recruits the membrane-shaping ESCRT-III proteins IST1 and CHMP1B to LDs via its MIT domain to facilitate LD-to-peroxisome FA trafficking, possibly through IST1- and CHMP1B-dependent modifications in LD membrane morphology. Furthermore, LD-to-peroxisome FA trafficking mediated by M1 Spastin is required to relieve LDs of lipid peroxidation. M1 Spastin’s dual roles in tethering LDs to peroxisomes and in recruiting ESCRT-III components to LD–peroxisome contact sites for FA trafficking may underlie the pathogenesis of diseases associated with defective FA metabolism in LDs and peroxisomes.
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South, Sarah T., Katherine A. Sacksteder, Xiaoling Li, Yifei Liu i Stephen J. Gould. "Inhibitors of Copi and Copii Do Not Block PEX3-Mediated Peroxisome Synthesis". Journal of Cell Biology 149, nr 7 (26.06.2000): 1345–60. http://dx.doi.org/10.1083/jcb.149.7.1345.
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In humans, defects in peroxisome biogenesis are the cause of lethal diseases typified by Zellweger syndrome. Here, we show that inactivating mutations in human PEX3 cause Zellweger syndrome, abrogate peroxisome membrane synthesis, and result in reduced abundance of peroxisomal membrane proteins (PMPs) and/or mislocalization of PMPs to the mitochondria. Previous studies have suggested that PEX3 may traffic through the ER en route to the peroxisome, that the COPI inhibitor, brefeldin A, leads to accumulation of PEX3 in the ER, and that PEX3 overexpression alters the morphology of the ER. However, we were unable to detect PEX3 in the ER at early times after expression. Furthermore, we find that inhibition of COPI function by brefeldin A has no effect on trafficking of PEX3 to peroxisomes and does not inhibit PEX3-mediated peroxisome biogenesis. We also find that inhibition of COPII-dependent membrane traffic by a dominant negative SAR1 mutant fails to block PEX3 transport to peroxisomes and PEX3-mediated peroxisome synthesis. Based on these results, we propose that PEX3 targeting to peroxisomes and PEX3-mediated peroxisome membrane synthesis may occur independently of COPI- and COPII-dependent membrane traffic.
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Zhang, J. W., C. Luckey i P. B. Lazarow. "Three peroxisome protein packaging pathways suggested by selective permeabilization of yeast mutants defective in peroxisome biogenesis." Molecular Biology of the Cell 4, nr 12 (grudzień 1993): 1351–59. http://dx.doi.org/10.1091/mbc.4.12.1351.
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We have identified five complementation groups of peroxisome biogenesis (peb) mutants in Saccharomyces cerevisiae by a positive selection procedure. Three of these contained morphologically recognizable peroxisomes, and two appeared to lack the organelle altogether. The packaging of peroxisomal proteins in these mutants has been analyzed with a new gentle cell fractionation procedure. It employs digitonin titration for the selective permeabilization of yeast plasma and intracellular membranes. Proteins were measured by enzymatic assay or by quantitative chemiluminescent immunoblotting. With this gentle fractionation method, it was demonstrated that two mutants are selectively defective in assembling proteins into peroxisomes. Peb1-1 packages catalase and acyl-CoA oxidase within peroxisomes but not thiolase. Peb5-1 packages thiolase and acyl-CoA oxidase within peroxisomes but not catalase. The data suggest that the peroxisome biogenesis machinery contains components that are specific for each of three classes of peroxisomal proteins, represented by catalase, thiolase, and acyl-CoA oxidase. In the two mutants lacking morphologically recognizable peroxisomes, peb2-1 and peb4-1, all three enzymes were mislocalized to the cytosol.
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Sacksteder, Katherine A., Jacob M. Jones, Sarah T. South, Xiaoling Li, Yifei Liu i Stephen J. Gould. "Pex19 Binds Multiple Peroxisomal Membrane Proteins, Is Predominantly Cytoplasmic, and Is Required for Peroxisome Membrane Synthesis". Journal of Cell Biology 148, nr 5 (6.03.2000): 931–44. http://dx.doi.org/10.1083/jcb.148.5.931.
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Peroxisomes are components of virtually all eukaryotic cells. While much is known about peroxisomal matrix protein import, our understanding of how peroxisomal membrane proteins (PMPs) are targeted and inserted into the peroxisome membrane is extremely limited. Here, we show that PEX19 binds a broad spectrum of PMPs, displays saturable PMP binding, and interacts with regions of PMPs required for their targeting to peroxisomes. Furthermore, mislocalization of PEX19 to the nucleus leads to nuclear accumulation of newly synthesized PMPs. At steady state, PEX19 is bimodally distributed between the cytoplasm and peroxisome, with most of the protein in the cytoplasm. We propose that PEX19 may bind newly synthesized PMPs and facilitate their insertion into the peroxisome membrane. This hypothesis is supported by the observation that the loss of PEX19 results in degradation of PMPs and/or mislocalization of PMPs to the mitochondrion.
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Chang, C. C., S. South, D. Warren, J. Jones, A. B. Moser, H. W. Moser i S. J. Gould. "Metabolic control of peroxisome abundance". Journal of Cell Science 112, nr 10 (15.05.1999): 1579–90. http://dx.doi.org/10.1242/jcs.112.10.1579.
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Zellweger syndrome and related disorders represent a group of lethal, genetically heterogeneous diseases. These peroxisome biogenesis disorders (PBDs) are characterized by defective peroxisomal matrix protein import and comprise at least 10 complementation groups. The genes defective in seven of these groups and more than 90% of PBD patients are now known. Here we examine the distribution of peroxisomal membrane proteins in fibroblasts from PBD patients representing the seven complementation groups for which the mutant gene is known. Peroxisomes were detected in all PBD cells, indicating that the ability to form a minimal peroxisomal structure is not blocked in these mutants. We also observed that peroxisome abundance was reduced fivefold in PBD cells that are defective in the PEX1, PEX5, PEX12, PEX6, PEX10, and PEX2 genes. These cell lines all display a defect in the import of proteins with the type-1 peroxisomal targeting signal (PTS1). In contrast, peroxisome abundance was unaffected in cells that are mutated in PEX7 and are defective only in the import of proteins with the type-2 peroxisomal targeting signal. Interestingly, a fivefold reduction in peroxisome abundance was also observed for cells lacking either of two PTS1-targeted peroxisomal beta-oxidation enzymes, acyl-CoA oxidase and 2-enoyl-CoA hydratase/D-3-hydroxyacyl-CoA dehydrogenase. These results indicate that reduced peroxisome abundance in PBD cells may be caused by their inability to import these PTS1-containing enzymes. Furthermore, the fact that peroxisome abundance is influenced by peroxisomal 105-oxidation activities suggests that there may be metabolic control of peroxisome abundance.
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Fagarasanu, Monica, Andrei Fagarasanu, Yuen Yi C. Tam, John D. Aitchison i Richard A. Rachubinski. "Inp1p is a peroxisomal membrane protein required for peroxisome inheritance in Saccharomyces cerevisiae". Journal of Cell Biology 169, nr 5 (31.05.2005): 765–75. http://dx.doi.org/10.1083/jcb.200503083.
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Cells have evolved molecular mechanisms for the efficient transmission of organelles during cell division. Little is known about how peroxisomes are inherited. Inp1p is a peripheral membrane protein of peroxisomes of Saccharomyces cerevisiae that affects both the morphology of peroxisomes and their partitioning during cell division. In vivo 4-dimensional video microscopy showed an inability of mother cells to retain a subset of peroxisomes in dividing cells lacking the INP1 gene, whereas cells overexpressing INP1 exhibited immobilized peroxisomes that failed to be partitioned to the bud. Overproduced Inp1p localized to both peroxisomes and the cell cortex, supporting an interaction of Inp1p with specific structures lining the cell periphery. The levels of Inp1p vary with the cell cycle. Inp1p binds Pex25p, Pex30p, and Vps1p, which have been implicated in controlling peroxisome division. Our findings are consistent with Inp1p acting as a factor that retains peroxisomes in cells and controls peroxisome division. Inp1p is the first peroxisomal protein directly implicated in peroxisome inheritance.
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Kim, Peter K., Robert T. Mullen, Uwe Schumann i Jennifer Lippincott-Schwartz. "The origin and maintenance of mammalian peroxisomes involves a de novo PEX16-dependent pathway from the ER". Journal of Cell Biology 173, nr 4 (22.05.2006): 521–32. http://dx.doi.org/10.1083/jcb.200601036.
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Peroxisomes are ubiquitous organelles that proliferate under different physiological conditions and can form de novo in cells that lack them. The endoplasmic reticulum (ER) has been shown to be the source of peroxisomes in yeast and plant cells. It remains unclear, however, whether the ER has a similar role in mammalian cells and whether peroxisome division or outgrowth from the ER maintains peroxisomes in growing cells. We use a new in cellula pulse-chase imaging protocol with photoactivatable GFP to investigate the mechanism underlying the biogenesis of mammalian peroxisomes. We provide direct evidence that peroxisomes can arise de novo from the ER in both normal and peroxisome-less mutant cells. We further show that PEX16 regulates this process by being cotranslationally inserted into the ER and serving to recruit other peroxisomal membrane proteins to membranes. Finally, we demonstrate that the increase in peroxisome number in growing wild-type cells results primarily from new peroxisomes derived from the ER rather than by division of preexisting peroxisomes.
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Hoepfner, Dominic, Marlene van den Berg, Peter Philippsen, Henk F. Tabak i Ewald H. Hettema. "A role for Vps1p, actin, and the Myo2p motor in peroxisome abundance and inheritance in Saccharomyces cerevisiae". Journal of Cell Biology 155, nr 6 (3.12.2001): 979–90. http://dx.doi.org/10.1083/jcb.200107028.
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In vivo time-lapse microscopy reveals that the number of peroxisomes in Saccharomyces cerevisiae cells is fairly constant and that a subset of the organelles are targeted and segregated to the bud in a highly ordered, vectorial process. The dynamin-like protein Vps1p controls the number of peroxisomes, since in a vps1Δ mutant only one or two giant peroxisomes remain. Analogous to the function of other dynamin-related proteins, Vps1p may be involved in a membrane fission event that is required for the regulation of peroxisome abundance. We found that efficient segregation of peroxisomes from mother to bud is dependent on the actin cytoskeleton, and active movement of peroxisomes along actin filaments is driven by the class V myosin motor protein, Myo2p: (a) peroxisomal dynamics always paralleled the polarity of the actin cytoskeleton, (b) double labeling of peroxisomes and actin cables revealed a close association between both, (c) depolymerization of the actin cytoskeleton abolished all peroxisomal movements, and (d) in cells containing thermosensitive alleles of MYO2, all peroxisome movement immediately stopped at the nonpermissive temperature. In addition, time-lapse videos showing peroxisome movement in wild-type and vps1Δ cells suggest the existence of various levels of control involved in the partitioning of peroxisomes.
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Tower, Robert J., Andrei Fagarasanu, John D. Aitchison i Richard A. Rachubinski. "The peroxin Pex34p functions with the Pex11 family of peroxisomal divisional proteins to regulate the peroxisome population in yeast". Molecular Biology of the Cell 22, nr 10 (15.05.2011): 1727–38. http://dx.doi.org/10.1091/mbc.e11-01-0084.
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Peroxisomes are ubiquitous organelles involved in diverse metabolic processes, most notably the metabolism of lipids and the detoxification of reactive oxygen species. Peroxisomes are highly dynamic and change in size and number in response to both intra- and extracellular cues. In the yeast Saccharomyces cerevisiae, peroxisome growth and division are controlled by both the differential import of soluble matrix proteins and a specialized divisional machinery that includes peroxisome-specific factors, such as members of the Pex11 protein family, and general organelle divisional factors, such as the dynamin-related protein Vps1p. Global yeast two-hybrid analyses have demonstrated interactions between the product of the S. cerevisiae gene of unknown function, YCL056c, and Pex proteins involved in peroxisome biogenesis. Here we show that the protein encoded by YCL056c, renamed Pex34p, is a peroxisomal integral membrane protein that acts independently and also in concert with the Pex11 protein family members Pex11p, Pex25p, and Pex27p to control the peroxisome populations of cells under conditions of both peroxisome proliferation and constitutive peroxisome division. Yeast two-hybrid analysis showed that Pex34p interacts physically with itself and with Pex11p, Pex25p, and Pex27p but not with Vps1p. Pex34p can act as a positive effector of peroxisome division as its overexpression leads to increased numbers of peroxisomes in wild type and pex34Δ cells. Pex34p requires the Pex11 family proteins to promote peroxisome division. Our discovery of Pex34p as a protein involved in the already complex control of peroxisome populations emphasizes the necessity of cells to strictly regulate their peroxisome populations to be able to respond appropriately to changing environmental conditions.
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Joshi, Saurabh, Gaurav Agrawal i Suresh Subramani. "Phosphorylation-dependent Pex11p and Fis1p interaction regulates peroxisome division". Molecular Biology of the Cell 23, nr 7 (kwiecień 2012): 1307–15. http://dx.doi.org/10.1091/mbc.e11-09-0782.
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Peroxisome division is regulated by the conserved peroxin Pex11p. In Saccharomyces cerevisiae (Sc), induction of the phosphoprotein ScPex11p coincides with peroxisome biogenesis. We show that the ScPex11p homologue in Pichia pastoris (PpPex11p) is phosphorylated at serine 173. PpPex11p expression and phosphorylation are induced in oleate and coordinated with peroxisome biogenesis. PpPex11p transits to peroxisomes via the endoplasmic reticulum (ER). PpPex11p is unstable and ER restricted gin pex3Δ and pex19Δ cells, which are impaired in peroxisomal membrane protein biogenesis. In oleate medium, the P. pastoris mutants pex11A (constitutively unphosphorylated; S173A) and pex11D (constitutively phosphorylated; S173D) exhibit juxtaposed elongated peroxisomes (JEPs) and hyperdivided forms, respectively, although protein levels remain unchanged. In contrast with ScPex11p, the ER-to-peroxisome translocation in P. pastoris is phosphorylation independent, and the phosphorylation occurs at the peroxisome. We show that PpPex11p interacts with the peroxisome fission machinery via PpFis1p and is regulated by phosphorylation because PpPex11p and PpPex11Dp interact more strongly with PpFis1p than PpPex11Ap. Neither PpPex11p nor PpFis1p is necessary for peroxisome division in methanol medium. We propose a model for the role of PpPex11p in the regulation of peroxisome division through a phosphorylation-dependent interaction with the fission machinery, providing novel insights into peroxisome morphogenesis.
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Hua, Rong, Derrick Cheng, Étienne Coyaud, Spencer Freeman, Erminia Di Pietro, Yuqing Wang, Adriano Vissa i in. "VAPs and ACBD5 tether peroxisomes to the ER for peroxisome maintenance and lipid homeostasis". Journal of Cell Biology 216, nr 2 (20.01.2017): 367–77. http://dx.doi.org/10.1083/jcb.201608128.
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Lipid exchange between the endoplasmic reticulum (ER) and peroxisomes is necessary for the synthesis and catabolism of lipids, the trafficking of cholesterol, and peroxisome biogenesis in mammalian cells. However, how lipids are exchanged between these two organelles is not understood. In this study, we report that the ER-resident VAMP-associated proteins A and B (VAPA and VAPB) interact with the peroxisomal membrane protein acyl-CoA binding domain containing 5 (ACBD5) and that this interaction is required to tether the two organelles together, thereby facilitating the lipid exchange between them. Depletion of either ACBD5 or VAP expression results in increased peroxisome mobility, suggesting that VAP–ACBD5 complex acts as the primary ER–peroxisome tether. We also demonstrate that tethering of peroxisomes to the ER is necessary for peroxisome growth, the synthesis of plasmalogen phospholipids, and the maintenance of cellular cholesterol levels. Collectively, our data highlight the importance of VAP–ACBD5–mediated contact between the ER and peroxisomes for organelle maintenance and lipid homeostasis.
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Gould, S. J., J. E. Kalish, J. C. Morrell, J. Bjorkman, A. J. Urquhart i D. I. Crane. "Pex13p is an SH3 protein of the peroxisome membrane and a docking factor for the predominantly cytoplasmic PTs1 receptor." Journal of Cell Biology 135, nr 1 (1.10.1996): 85–95. http://dx.doi.org/10.1083/jcb.135.1.85.
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Import of newly synthesized PTS1 proteins into the peroxisome requires the PTS1 receptor (Pex5p), a predominantly cytoplasmic protein that cycles between the cytoplasm and peroxisome. We have identified Pex13p, a novel integral peroxisomal membrane from both yeast and humans that binds the PTS1 receptor via a cytoplasmically oriented SH3 domain. Although only a small amount of Pex5p is bound to peroxisomes at steady state (< 5%), loss of Pex13p further reduces the amount of peroxisome-associated Pex5p by approximately 40-fold. Furthermore, loss of Pex13p eliminates import of peroxisomal matrix proteins that contain either the type-1 or type-2 peroxisomal targeting signal but does not affect targeting and insertion of integral peroxisomal membrane proteins. We conclude that Pex13p functions as a docking factor for the predominantly cytoplasmic PTS1 receptor.
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Kalish, J. E., C. Theda, J. C. Morrell, J. M. Berg i S. J. Gould. "Formation of the peroxisome lumen is abolished by loss of Pichia pastoris Pas7p, a zinc-binding integral membrane protein of the peroxisome." Molecular and Cellular Biology 15, nr 11 (listopad 1995): 6406–19. http://dx.doi.org/10.1128/mcb.15.11.6406.
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We have cloned and sequenced PAS7, a gene required for peroxisome assembly in the yeast Pichia pastoris. The product of this gene, Pas7p, is a member of the C3HC4 superfamily of zinc-binding proteins. Point mutations that alter conserved residues of the C3HC4 motif abolish PAS7 activity and reduce zinc binding, suggesting that Pas7p binds zinc in vivo and that zinc binding is essential for PAS7 function. As with most pas mutants, pas7 cells exhibit a pronounced deficiency in import of peroxisomal matrix proteins that contain either the type 1 peroxisomal targeting signal (PTS1) or the type 2 PTS (PTS2). However, while other yeast and mammalian pas mutants accumulate ovoid, vesicular peroxisomal intermediates, loss of Pas7p leads to accumulation of membrane sheets and vesicles which lack a recognizable lumen. Thus, Pas7p appears to be essential for protein translocation into peroxisomes as well as formation of the lumen of the organelle. Consistent with these data, we find that Pas7p is an integral peroxisomal membrane protein which is entirely resistant to exogenous protease and thus appears to reside completely within the peroxisome. Our observations suggest that the function of Pas7p defines a previously unrecognized step in peroxisome assembly: formation of the peroxisome lumen. Furthermore, because the peroxisomal intermediates in the pas7 delta mutant proliferate in response to peroxisome-inducing environmental conditions, we conclude that Pas7p is not required for peroxisome proliferation.
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Escaño, Cristopher Salazar, Praveen Rao Juvvadi, Feng Jie Jin, Tadashi Takahashi, Yasuji Koyama, Shuichi Yamashita, Jun-ichi Maruyama i Katsuhiko Kitamoto. "Disruption of the Aopex11-1 Gene Involved in Peroxisome Proliferation Leads to Impaired Woronin Body Formation in Aspergillus oryzae". Eukaryotic Cell 8, nr 3 (9.01.2009): 296–305. http://dx.doi.org/10.1128/ec.00197-08.
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ABSTRACT The Woronin body, a unique organelle found in the Pezizomycotina, plugs the septal pore upon hyphal damage to prevent excessive cytoplasmic bleeding. Although it was previously shown that the Woronin body buds out from the peroxisome, the relationship between peroxisomal proliferation/division and Woronin body differentiation has not been extensively investigated. In this report, we examined whether Pex11 required for peroxisomal proliferation participates in Woronin body formation in Aspergillus oryzae. A. oryzae contained two orthologous PEX11 genes that were designated Aopex11-1 and Aopex11-2. Deletion of Aopex11 genes revealed that only the ΔAopex11-1 strain showed reduced growth and enlarged peroxisomes in the presence of oleic acid as a sole carbon source, indicating a defect in peroxisomal function and proliferation. Disruption of Aopex11-1 gene impaired the Woronin body function, leading to excessive loss of the cytosol upon hyphal injury. Dual localization analysis of the peroxisome and Woronin body protein AoHex1 demonstrated that Woronin bodies fail to fully differentiate from peroxisomes in the ΔAopex11-1 strain. Furthermore, distribution of AoHex1 was found to be peripheral in the enlarged peroxisome or junctional in dumbbell-shaped peroxisomes. Electron microscopy of the ΔAopex11-1 strain revealed the presence of Woronin bodies that remained associated with organelles resembling peroxisomes, which was supported from the sucrose gradient centrifugation confirming that the Woronin body protein AoHex1 overlapped with the density-shifted peroxisome in the ΔAopex11-1 strain. In conclusion, the present study describes the role of Pex11 in Woronin body differentiation for the first time.
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Gonzalez, Kim L., Sarah E. Ratzel, Kendall H. Burks, Charles H. Danan, Jeanne M. Wages, Bethany K. Zolman i Bonnie Bartel. "A pex1 missense mutation improves peroxisome function in a subset of Arabidopsis pex6 mutants without restoring PEX5 recycling". Proceedings of the National Academy of Sciences 115, nr 14 (19.03.2018): E3163—E3172. http://dx.doi.org/10.1073/pnas.1721279115.
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Peroxisomes are eukaryotic organelles critical for plant and human development because they house essential metabolic functions, such as fatty acid β-oxidation. The interacting ATPases PEX1 and PEX6 contribute to peroxisome function by recycling PEX5, a cytosolic receptor needed to import proteins targeted to the peroxisomal matrix. Arabidopsis pex6 mutants exhibit low PEX5 levels and defects in peroxisomal matrix protein import, oil body utilization, peroxisomal metabolism, and seedling growth. These defects are hypothesized to stem from impaired PEX5 retrotranslocation leading to PEX5 polyubiquitination and consequent degradation of PEX5 via the proteasome or of the entire organelle via autophagy. We recovered a pex1 missense mutation in a screen for second-site suppressors that restore growth to the pex6-1 mutant. Surprisingly, this pex1-1 mutation ameliorated the metabolic and physiological defects of pex6-1 without restoring PEX5 levels. Similarly, preventing autophagy by introducing an atg7-null allele partially rescued pex6-1 physiological defects without restoring PEX5 levels. atg7 synergistically improved matrix protein import in pex1-1 pex6-1, implying that pex1-1 improves peroxisome function in pex6-1 without impeding autophagy of peroxisomes (i.e., pexophagy). pex1-1 differentially improved peroxisome function in various pex6 alleles but worsened the physiological and molecular defects of a pex26 mutant, which is defective in the tether anchoring the PEX1–PEX6 hexamer to the peroxisome. Our results support the hypothesis that, beyond PEX5 recycling, PEX1 and PEX6 have additional functions in peroxisome homeostasis and perhaps in oil body utilization.
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Geuze, Hans J., Jean Luc Murk, An K. Stroobants, Janice M. Griffith, Monique J. Kleijmeer, Abraham J. Koster, Arie J. Verkleij, Ben Distel i Henk F. Tabak. "Involvement of the Endoplasmic Reticulum in Peroxisome Formation". Molecular Biology of the Cell 14, nr 7 (lipiec 2003): 2900–2907. http://dx.doi.org/10.1091/mbc.e02-11-0734.
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The traditional view holds that peroxisomes are autonomous organelles multiplying by growth and division. More recently, new observations have challenged this concept. Herein, we present evidence supporting the involvement of the endoplasmic reticulum (ER) in peroxisome formation by electron microscopy, immunocytochemistry and three-dimensional image reconstruction of peroxisomes and associated compartments in mouse dendritic cells. We found the peroxisomal membrane protein Pex13p and the ATP-binding cassette transporter protein PMP70 present in specialized subdomains of the ER that were continuous with a peroxisomal reticulum from which mature peroxisomes arose. The matrix proteins catalase and thiolase were only detectable in the reticula and peroxisomes. Our results suggest the existence of a maturation pathway from the ER to peroxisomes and implicate the ER as a major source from which the peroxisomal membrane is derived.
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Colasante, Claudia, Jiangping Chen, Barbara Ahlemeyer i Eveline Baumgart-Vogt. "Peroxisomes in cardiomyocytes and the peroxisome / peroxisome proliferator-activated receptor-loop". Thrombosis and Haemostasis 113, nr 03 (maj 2015): 452–63. http://dx.doi.org/10.1160/th14-06-0497.
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SummaryIt is well established that the heart is strongly dependent on fatty acid metabolism. In cardiomyocytes there are two distinct sites for the β-oxidisation of fatty acids: the mitochondrion and the peroxisome. Although the metabolism of these two organelles is believed to be tightly coupled, the nature of this relationship has not been fully investigated. Recent research has established the significant contribution of mitochondrial function to cardiac ATP production under normal and pathological conditions. In contrast, limited information is available on peroxisomal function in the heart. This is despite these organelles harbouring metabolic pathways that are potentially cardioprotective, and findings that patients with peroxisomal diseases, such as adult Refsum’s disease, can develop heart failure. In this article, we provide a comprehensive overview on the current knowledge of peroxisomes and the regulation of lipid metabolism by PPARs in cardiomyocytes. We also present new experimental evidence on the differential expression of peroxisome-related genes in the heart chambers and demonstrate that even a mild peroxisomal biogenesis defect (Pex11α-/- ) can induce profound alterations in the cardiomyocyte’s peroxisomal compartment and related gene expression, including the concomitant deregulation of specific PPARs. The possible impact of peroxisomal dysfunction in the heart is discussed and a model for the modulation of myocardial metabolism via a peroxisome/PPAR-loop is proposed.
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Fang, Yi, James C. Morrell, Jacob M. Jones i Stephen J. Gould. "PEX3 functions as a PEX19 docking factor in the import of class I peroxisomal membrane proteins". Journal of Cell Biology 164, nr 6 (8.03.2004): 863–75. http://dx.doi.org/10.1083/jcb.200311131.
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PEX19 is a chaperone and import receptor for newly synthesized, class I peroxisomal membrane proteins (PMPs). PEX19 binds these PMPs in the cytoplasm and delivers them to the peroxisome for subsequent insertion into the peroxisome membrane, indicating that there may be a PEX19 docking factor in the peroxisome membrane. Here we show that PEX3 is required for PEX19 to dock at peroxisomes, interacts specifically with the docking domain of PEX19, and is required for recruitment of the PEX19 docking domain to peroxisomes. PEX3 is also sufficient to dock PEX19 at heterologous organelles and binds PEX19 via a conserved motif that is essential for this docking activity and for PEX3 function in general. Not surprisingly, transient inhibition of PEX3 abrogates class I PMP import but has no effect on class II PMP import or peroxisomal matrix protein import. Taken together, these results suggest that PEX3 plays a selective, essential, and direct role in PMP import as a docking factor for PEX19.
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Watanabe, T., N. D. Lalwani i J. K. Reddy. "Specific changes in the protein composition of rat liver in response to the peroxisome proliferators ciprofibrate, Wy-14,643 and di-(2-ethylhexyl)phthalate". Biochemical Journal 227, nr 3 (1.05.1985): 767–75. http://dx.doi.org/10.1042/bj2270767.
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The hypolipidaemic agents ciprofibrate and Wy-14,643 ([4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio]acetic acid) and the phthalate-ester plasticizer di-(2-ethylhexyl)-phthalate (DEHP), like other peroxisome proliferators, produce a significant hepatomegaly and induce the peroxisomal fatty acid beta-oxidation enzyme system together with profound proliferation of peroxisomes in hepatic parenchymal cells. Changes in the profile of liver proteins in rats following induction of peroxisome proliferation by ciprofibrate, Wy-14,643 and DEHP have been analysed by high-resolution two-dimensional gel electrophoresis. The proteins of whole liver homogenates from normal and peroxisome-proliferator-treated rats were separated by two-dimensional gel electrophoresis using isoelectric focusing for acidic proteins and nonequilibrium pH gradient electrophoresis for basic proteins. In the whole liver homogenates, the quantities of six proteins in acidic gels and six proteins in the basic gels increased following induction of peroxisome proliferation. Peroxisome proliferator administration caused a repression of three acidic proteins in the liver homogenates. By the immunoblot method using polyspecific antiserum against soluble peroxisomal proteins and monospecific antiserum against peroxisome proliferation associated Mr 80000 polypeptide (polypeptide PPA-80), the majority of basic proteins induced by these peroxisome proliferators appeared to be peroxisomal proteins. Polypeptide PPA-80 becomes the most abundant protein in the total liver homogenates of peroxisome-proliferator-treated rats. These results indicate that ciprofibrate, DEHP and Wy-14,643 induce marked changes in the profile of specific hepatic proteins and that some of these changes should serve as a baseline to identify a set of gene products that may assist in defining the specific ‘peroxisome proliferator domain’.
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Mast, Fred D., Thurston Herricks, Kathleen M. Strehler, Leslie R. Miller, Ramsey A. Saleem, Richard A. Rachubinski i John D. Aitchison. "ESCRT-III is required for scissioning new peroxisomes from the endoplasmic reticulum". Journal of Cell Biology 217, nr 6 (27.03.2018): 2087–102. http://dx.doi.org/10.1083/jcb.201706044.
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Dynamic control of peroxisome proliferation is integral to the peroxisome’s many functions. The endoplasmic reticulum (ER) serves as a source of preperoxisomal vesicles (PPVs) that mature into peroxisomes during de novo peroxisome biogenesis and support growth and division of existing peroxisomes. However, the mechanism of PPV formation and release from the ER remains poorly understood. In this study, we show that endosomal sorting complexes required for transport (ESCRT)-III are required to release PPVs budding from the ER into the cytosol. Absence of ESCRT-III proteins impedes de novo peroxisome formation and results in an aberrant peroxisome population in vivo. Using a cell-free PPV budding assay, we show that ESCRT-III proteins Vps20 and Snf7 are necessary to release PPVs from the ER. ESCRT-III is therefore a positive effector of membrane scission for vesicles budding both away from and toward the cytosol. These findings have important implications for the evolutionary timing of emergence of peroxisomes and the rest of the internal membrane architecture of the eukaryotic cell.
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Mbekeani, Alison, Will Stanley, Vishal Kalel, Noa Dahan, Einat Zalckvar, Lilach Sheiner, Wolfgang Schliebs, Ralf Erdmann, Ehmke Pohl i Paul Denny. "Functional Analyses of a Putative, Membrane-Bound, Peroxisomal Protein Import Mechanism from the Apicomplexan Protozoan Toxoplasma gondii". Genes 9, nr 9 (29.08.2018): 434. http://dx.doi.org/10.3390/genes9090434.
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Peroxisomes are central to eukaryotic metabolism, including the oxidation of fatty acids—which subsequently provide an important source of metabolic energy—and in the biosynthesis of cholesterol and plasmalogens. However, the presence and nature of peroxisomes in the parasitic apicomplexan protozoa remains controversial. A survey of the available genomes revealed that genes encoding peroxisome biogenesis factors, so-called peroxins (Pex), are only present in a subset of these parasites, the coccidia. The basic principle of peroxisomal protein import is evolutionarily conserved, proteins harbouring a peroxisomal-targeting signal 1 (PTS1) interact in the cytosol with the shuttling receptor Pex5 and are then imported into the peroxisome via the membrane-bound protein complex formed by Pex13 and Pex14. Surprisingly, whilst Pex5 is clearly identifiable, Pex13 and, perhaps, Pex14 are apparently absent from the coccidian genomes. To investigate the functionality of the PTS1 import mechanism in these parasites, expression of Pex5 from the model coccidian Toxoplasma gondii was shown to rescue the import defect of Pex5-deleted Saccharomyces cerevisiae. In support of these data, green fluorescent protein (GFP) bearing the enhanced (e)PTS1 known to efficiently localise to peroxisomes in yeast, localised to peroxisome-like bodies when expressed in Toxoplasma. Furthermore, the PTS1-binding domain of Pex5 and a PTS1 ligand from the putatively peroxisome-localised Toxoplasma sterol carrier protein (SCP2) were shown to interact in vitro. Taken together, these data demonstrate that the Pex5–PTS1 interaction is functional in the coccidia and indicate that a nonconventional peroxisomal import mechanism may operate in the absence of Pex13 and Pex14.
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Walker, Cheryl L., Laura C. D. Pomatto, Durga Nand Tripathi i Kelvin J. A. Davies. "Redox Regulation of Homeostasis and Proteostasis in Peroxisomes". Physiological Reviews 98, nr 1 (1.01.2018): 89–115. http://dx.doi.org/10.1152/physrev.00033.2016.
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Peroxisomes are highly dynamic intracellular organelles involved in a variety of metabolic functions essential for the metabolism of long-chain fatty acids, d-amino acids, and many polyamines. A byproduct of peroxisomal metabolism is the generation, and subsequent detoxification, of reactive oxygen and nitrogen species, particularly hydrogen peroxide (H2O2). Because of its relatively low reactivity (as a mild oxidant), H2O2 has a comparatively long intracellular half-life and a high diffusion rate, all of which makes H2O2 an efficient signaling molecule. Peroxisomes also have intricate connections to mitochondria, and both organelles appear to play important roles in regulating redox signaling pathways. Peroxisomal proteins are also subject to oxidative modification and inactivation by the reactive oxygen and nitrogen species they generate, but the peroxisomal LonP2 protease can selectively remove such oxidatively damaged proteins, thus prolonging the useful lifespan of the organelle. Peroxisomal homeostasis must adapt to the metabolic state of the cell, by a combination of peroxisome proliferation, the removal of excess or badly damaged organelles by autophagy (pexophagy), as well as by processes of peroxisome inheritance and motility. More recently the tumor suppressors ataxia telangiectasia mutate (ATM) and tuberous sclerosis complex (TSC), which regulate mTORC1 signaling, have been found to regulate pexophagy in response to variable levels of certain reactive oxygen and nitrogen species. It is now clear that any significant loss of peroxisome homeostasis can have devastating physiological consequences. Peroxisome dysregulation has been implicated in several metabolic diseases, and increasing evidence highlights the important role of diminished peroxisomal functions in aging processes.
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Huang, Lichao, Yijing Liu, Xiaqin Wang, Cheng Jiang, Yanqiu Zhao, Mengzhu Lu i Jin Zhang. "Peroxisome-Mediated Reactive Oxygen Species Signals Modulate Programmed Cell Death in Plants". International Journal of Molecular Sciences 23, nr 17 (3.09.2022): 10087. http://dx.doi.org/10.3390/ijms231710087.
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Peroxisomes are a class of simple organelles that play an important role in plant reactive oxygen species (ROS) metabolism. Experimental evidence reveals the involvement of ROS in programmed cell death (PCD) in plants. Plant PCD is crucial for the regulation of plant growth, development and environmental stress resistance. However, it is unclear whether the ROS originated from peroxisomes participated in cellular PCD. Enzymes involved in the peroxisomal ROS metabolic pathways are key mediators to figure out the relationship between peroxisome-derived ROS and PCD. Here, we summarize the peroxisomal ROS generation and scavenging pathways and explain how peroxisome-derived ROS participate in PCD based on recent progress in the functional study of enzymes related to peroxisomal ROS generation or scavenging. We aimed to elucidate the role of the peroxisomal ROS regulatory system in cellular PCD to show its potential in terms of accurate PCD regulation, which contribute to environmental stress resistance.
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Titorenko, Vladimir I., Honey Chan i Richard A. Rachubinski. "Fusion of Small Peroxisomal Vesicles in Vitro Reconstructs an Early Step in the in Vivo Multistep Peroxisome Assembly Pathway of Yarrowia lipolytica". Journal of Cell Biology 148, nr 1 (10.01.2000): 29–44. http://dx.doi.org/10.1083/jcb.148.1.29.
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We have identified and purified six subforms of peroxisomes, designated P1 to P6, from the yeast, Yarrowia lipolytica. An analysis of trafficking of peroxisomal proteins in vivo suggests the existence of a multistep peroxisome assembly pathway in Y. lipolytica. This pathway operates by conversion of peroxisomal subforms in the direction P1, P2→P3→P4→P5→P6 and involves the import of various peroxisomal proteins into distinct vesicular intermediates. We have also reconstituted in vitro the fusion of the earliest intermediates in the pathway, small peroxisomal vesicles P1 and P2. Their fusion leads to the formation of a larger and more dense peroxisomal vesicle, P3. Fusion of P1 and P2 in vitro requires cytosol and ATP hydrolysis and is inhibited by antibodies to two membrane-associated ATPases of the AAA family, Pex1p and Pex6p. We provide evidence that the fusion in vitro of P1 and P2 peroxisomes reconstructs an actual early step in the peroxisome assembly pathway operating in vivo in Y. lipolytica.
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Behera, Ananyaashree, Preeti Jain, Geetanjali Ganguli, Mainak Biswas, Avinash Padhi, Kali Prasad Pattanaik, Barsa Nayak i in. "Mycobacterium tuberculosis Acetyltransferase Suppresses Oxidative Stress by Inducing Peroxisome Formation in Macrophages". International Journal of Molecular Sciences 23, nr 5 (26.02.2022): 2584. http://dx.doi.org/10.3390/ijms23052584.
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Mycobacterium tuberculosis (Mtb) inhibits host oxidative stress responses facilitating its survival in macrophages; however, the underlying molecular mechanisms are poorly understood. Here, we identified a Mtb acetyltransferase (Rv3034c) as a novel counter actor of macrophage oxidative stress responses by inducing peroxisome formation. An inducible Rv3034c deletion mutant of Mtb failed to induce peroxisome biogenesis, expression of the peroxisomal β-oxidation pathway intermediates (ACOX1, ACAA1, MFP2) in macrophages, resulting in reduced intracellular survival compared to the parental strain. This reduced virulence phenotype was rescued by repletion of Rv3034c. Peroxisome induction depended on the interaction between Rv3034c and the macrophage mannose receptor (MR). Interaction between Rv3034c and MR induced expression of the peroxisomal biogenesis proteins PEX5p, PEX13p, PEX14p, PEX11β, PEX19p, the peroxisomal membrane lipid transporter ABCD3, and catalase. Expression of PEX14p and ABCD3 was also enhanced in lungs from Mtb aerosol-infected mice. This is the first report that peroxisome-mediated control of ROS balance is essential for innate immune responses to Mtb but can be counteracted by the mycobacterial acetyltransferase Rv3034c. Thus, peroxisomes represent interesting targets for host-directed therapeutics to tuberculosis.
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Wu, Fei, Rinse de Boer, Arjen M. Krikken, Arman Akşit, Nicola Bordin, Damien P. Devos i Ida J. van der Klei. "Pex24 and Pex32 are required to tether peroxisomes to the ER for organelle biogenesis, positioning and segregation in yeast". Journal of Cell Science 133, nr 16 (14.07.2020): jcs246983. http://dx.doi.org/10.1242/jcs.246983.
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ABSTRACTThe yeast Hansenula polymorpha contains four members of the Pex23 family of peroxins, which characteristically contain a DysF domain. Here we show that all four H. polymorpha Pex23 family proteins localize to the endoplasmic reticulum (ER). Pex24 and Pex32, but not Pex23 and Pex29, predominantly accumulate at peroxisome–ER contacts. Upon deletion of PEX24 or PEX32 – and to a much lesser extent, of PEX23 or PEX29 – peroxisome–ER contacts are lost, concomitant with defects in peroxisomal matrix protein import, membrane growth, and organelle proliferation, positioning and segregation. These defects are suppressed by the introduction of an artificial peroxisome–ER tether, indicating that Pex24 and Pex32 contribute to tethering of peroxisomes to the ER. Accumulation of Pex32 at these contact sites is lost in cells lacking the peroxisomal membrane protein Pex11, in conjunction with disruption of the contacts. This indicates that Pex11 contributes to Pex32-dependent peroxisome–ER contact formation. The absence of Pex32 has no major effect on pre-peroxisomal vesicles that occur in pex3 atg1 deletion cells.
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Weng, Huachun, Xu Ji, Yukiko Naito, Kosuke Endo, Xiao Ma, Rie Takahashi, Chunshen Shen, Go Hirokawa, Yasue Fukushima i Naoharu Iwai. "Pex11α deficiency impairs peroxisome elongation and division and contributes to nonalcoholic fatty liver in mice". American Journal of Physiology-Endocrinology and Metabolism 304, nr 2 (15.01.2013): E187—E196. http://dx.doi.org/10.1152/ajpendo.00425.2012.
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Hepatic triglyceride (TG) accumulation is considered to be a prerequisite for developing nonalcoholic fatty liver (NAFL). Peroxisomes have many important functions in lipid metabolism, including fatty acid β-oxidization. However, the pathogenic link between NAFL and peroxisome biogenesis remains unclear. To examine the molecular and physiological functions of the Pex11α gene, we disrupted this gene in mice. Body weights and hepatic TG concentrations in Pex11α−/− mice were significantly higher than those in wild-type (WT) mice fed a normal or a high-fat diet. Hepatic TG concentrations in fasted Pex11α−/− mice were significantly higher than those in fasted WT mice. Plasma TG levels increased at lower rates in Pex11α−/− mice than in WT mice after treatment with the lipoprotein lipase inhibitor tyloxapol. The number of peroxisomes was lower in the livers of Pex11α−/− mice than in those of WT mice. Ultrastructural analysis showed that small and regular spherically shaped peroxisomes were more prevalent in Pex11α−/− mice fed normal chow supplemented without or with fenofibrate. We observed a significantly higher ratio of empty peroxisomes containing only PMP70, a peroxisome membrane protein, but not catalase, a peroxisome matrix protein, in Pex11α−/− mice. The mRNA expression levels of peroxisomal fatty acid oxidation-related genes (ATP-binding cassette, subfamily D, member 2, and acyl-CoA thioesterase 3) were significantly higher in WT mice than those in Pex11α−/− mice under fed conditions. Our results demonstrate that Pex11α deficiency impairs peroxisome elongation and abundance and peroxisomal fatty acid oxidation, which contributes to increased lipid accumulation in the liver.