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Proceedings of the National Academy of... Mar 2009Peroxisomes are ubiquitous eukaryotic organelles housing diverse enzymatic reactions, including several that produce toxic reactive oxygen species. Although...
Peroxisomes are ubiquitous eukaryotic organelles housing diverse enzymatic reactions, including several that produce toxic reactive oxygen species. Although understanding of the mechanisms whereby enzymes enter peroxisomes with the help of peroxin (PEX) proteins is increasing, mechanisms by which damaged or obsolete peroxisomal proteins are degraded are not understood. We have exploited unique aspects of plant development to characterize peroxisome-associated protein degradation (PexAD) in Arabidopsis. Oilseed seedlings undergo a developmentally regulated remodeling of peroxisomal matrix protein composition in which the glyoxylate cycle enzymes isocitrate lyase (ICL) and malate synthase (MLS) are replaced by photorespiration enzymes. We found that mutations expected to increase or decrease peroxisomal H(2)O(2) levels accelerated or delayed ICL and MLS disappearance, respectively, suggesting that oxidative damage promotes peroxisomal protein degradation. ICL, MLS, and the beta-oxidation enzyme thiolase were stabilized in the pex4-1 pex22-1 double mutant, which is defective in a peroxisome-associated ubiquitin-conjugating enzyme and its membrane tether. Moreover, the stabilized ICL, thiolase, and an ICL-GFP reporter remained peroxisome associated in pex4-1 pex22-1. ICL also was stabilized and peroxisome associated in pex6-1, a mutant defective in a peroxisome-tethered ATPase. ICL and thiolase were mislocalized to the cytosol but only ICL was stabilized in pex5-10, a mutant defective in a matrix protein import receptor, suggesting that peroxisome entry is necessary for degradation of certain matrix proteins. Together, our data reveal new roles for PEX4, PEX5, PEX6, and PEX22 in PexAD of damaged or obsolete matrix proteins in addition to their canonical roles in peroxisome biogenesis.
Topics: Arabidopsis; Arabidopsis Proteins; Isocitrate Lyase; Malate Synthase; Peroxisomes; Protein Stability
PubMed: 19246395
DOI: 10.1073/pnas.0811329106 -
Mycologia 2016Peroxisomes are versatile and dynamic organelles that are required for the development of diverse eukaryotic organisms. We demonstrated previously that in the fungus...
Peroxisomes are versatile and dynamic organelles that are required for the development of diverse eukaryotic organisms. We demonstrated previously that in the fungus Podospora anserina different peroxisomal functions are required at distinct stages of sexual development, including the initiation and progression of meiocyte (ascus) development and the differentiation and germination of sexual spores (ascospores). Peroxisome assembly during these processes relies on the differential activity of the protein machinery that drives the import of proteins into the organelle, indicating a complex developmental regulation of peroxisome formation and activity. Here we demonstrate that peroxisome dynamics is also highly regulated during development. We show that peroxisomes in P. anserina are highly dynamic and respond to metabolic and environmental cues by undergoing changes in size, morphology and number. In addition, peroxisomes of vegetative and sexual cell types are structurally different. During sexual development peroxisome number increases at two stages: at early ascus differentiation and during ascospore formation. These processes are accompanied by changes in peroxisome structure and distribution, which include a cell-polarized concentration of peroxisomes at the beginning of ascus development, as well as a morphological transition from predominantly spherical to elongated shapes at the end of the first meiotic division. Further, the mostly tubular peroxisomes present from second meiotic division to early ascospore formation again become rounded during ascospore differentiation. Ultimately the number of peroxisomes dramatically decreases upon ascospore maturation. Our results reveal a precise regulation of peroxisome dynamics during sexual development and suggest that peroxisome constitution and function during development is defined by the coordinated regulation of the proteins that control peroxisome assembly and dynamics.
Topics: Fungal Proteins; Gene Expression Regulation, Developmental; Gene Expression Regulation, Fungal; Genes, Mating Type, Fungal; Peroxisomes; Podospora; Spores, Fungal
PubMed: 26908647
DOI: 10.3852/15-112 -
Sub-cellular Biochemistry 2018Peroxisome proliferation involves signal recognition and computation by molecular networks that direct molecular events of gene expression, metabolism, membrane... (Review)
Review
Peroxisome proliferation involves signal recognition and computation by molecular networks that direct molecular events of gene expression, metabolism, membrane biogenesis, organelle proliferation, protein import, and organelle inheritance. Peroxisome biogenesis in yeast has served as a model system for exploring the regulatory networks controlling this process. Yeast is an outstanding model system to develop tools and approaches to study molecular networks and cellular responses and because the mechanisms of peroxisome biogenesis and key aspects of the transcriptional regulatory networks are remarkably conserved from yeast to humans. In this chapter, we focus on the complex regulatory networks that respond to environmental cues leading to peroxisome assembly and the molecular events of organelle assembly. Ultimately, understanding the mechanisms of the entire peroxisome biogenesis program holds promise for predictive modeling approaches and for guiding rational intervention strategies that could treat human conditions associated with peroxisome function.
Topics: Humans; Metabolic Networks and Pathways; Models, Biological; Peroxisomes; Protein Transport; Saccharomyces cerevisiae
PubMed: 30378032
DOI: 10.1007/978-981-13-2233-4_16 -
Sub-cellular Biochemistry 2018Plant peroxisomes are required for a number of fundamental physiological processes, such as primary and secondary metabolism, development and stress response. Indexing... (Review)
Review
Plant peroxisomes are required for a number of fundamental physiological processes, such as primary and secondary metabolism, development and stress response. Indexing the dynamic peroxisome proteome is prerequisite to fully understanding the importance of these organelles. Mass Spectrometry (MS)-based proteome analysis has allowed the identification of novel peroxisomal proteins and pathways in a relatively high-throughput fashion and significantly expanded the list of proteins and biochemical reactions in plant peroxisomes. In this chapter, we summarize the experimental proteomic studies performed in plants, compile a list of ~200 confirmed Arabidopsis peroxisomal proteins, and discuss the diverse plant peroxisome functions with an emphasis on the role of Arabidopsis MS-based proteomics in discovering new peroxisome functions. Many plant peroxisome proteins and biochemical pathways are specific to plants, substantiating the complexity, plasticity and uniqueness of plant peroxisomes. Mapping the full plant peroxisome proteome will provide a knowledge base for the improvement of crop production, quality and stress tolerance.
Topics: Arabidopsis; Arabidopsis Proteins; Peroxisomes; Plant Cells; Proteome; Proteomics
PubMed: 30378017
DOI: 10.1007/978-981-13-2233-4_1 -
Biochimica Et Biophysica Acta Dec 2006The import of proteins into the peroxisome matrix is an essential step in peroxisome biogenesis, which is critical for normal functioning of most eukaryotic cells. The... (Review)
Review
The import of proteins into the peroxisome matrix is an essential step in peroxisome biogenesis, which is critical for normal functioning of most eukaryotic cells. The translocation of proteins across the peroxisome membrane and the dynamic behavior of the import receptors during the import cycle is facilitated by several peroxisome-membrane-associated protein complexes, one of which is called the importomer complex [B. Agne, N.M. Meindl, K. Niederhoff, H. Einwachter, P. Rehling, A. Sickmann, H.E. Meyer, W. Girzalsky, W.H. Kunau, Pex8p: an intraperoxisomal organizer of the peroxisomal import machinery, Mol. Cell 11 (2003) 635-646; P.P. Hazra, I. Suriapranata, W.B. Snyder, S. Subramani, Peroxisome remnants in pex3Delta cells and the requirement of Pex3p for interactions between the peroxisomal docking and translocation subcomplexes, Traffic 3 (2002) 560-574. ]. We provide below a brief historical perspective regarding the importomer and its role in peroxisome biogenesis. We also identify areas in which further work is needed to uncover the physiological role of the importomer.
Topics: Intracellular Membranes; Membrane Proteins; Membrane Transport Proteins; Peroxins; Peroxisomes; Protein Transport; Saccharomyces cerevisiae Proteins
PubMed: 17027097
DOI: 10.1016/j.bbamcr.2006.08.035 -
The Journal of Cell Biology Mar 2019The regulation of organelle abundance is critical for cell function and survival; however, the mechanisms responsible are not fully understood. In this study, we...
The regulation of organelle abundance is critical for cell function and survival; however, the mechanisms responsible are not fully understood. In this study, we characterize a role of the deubiquitinating enzyme USP30 in peroxisome maintenance. Peroxisomes are highly dynamic, changing in abundance in response to metabolic stress. In our recent study identifying the role of USP30 in mitophagy, we observed USP30 to be localized to punctate structures resembling peroxisomes. We report here that USP30, best known as a mitophagy regulator, is also necessary for regulating pexophagy, the selective autophagic degradation of peroxisomes. We find that overexpressing USP30 prevents pexophagy during amino acid starvation, and its depletion results in pexophagy induction under basal conditions. We demonstrate that USP30 prevents pexophagy by counteracting the action of the peroxisomal E3 ubiquitin ligase PEX2. Finally, we show that USP30 can rescue the peroxisome loss observed in some disease-causing peroxisome mutations, pointing to a potential therapeutic target.
Topics: Animals; COS Cells; Chlorocebus aethiops; HeLa Cells; Humans; Mice; Mitochondrial Proteins; Mitophagy; Mutation; Peroxisomal Biogenesis Factor 2; Peroxisomes; Stress, Physiological; Thiolester Hydrolases
PubMed: 30700497
DOI: 10.1083/jcb.201804172 -
Journal of Cell Science Aug 2023Peroxisomes are involved in a multitude of metabolic and catabolic pathways, as well as the innate immune system. Their dysfunction is linked to severe... (Review)
Review
Peroxisomes are involved in a multitude of metabolic and catabolic pathways, as well as the innate immune system. Their dysfunction is linked to severe peroxisome-specific diseases, as well as cancer and neurodegenerative diseases. To ensure the ability of peroxisomes to fulfill their many roles in the organism, more than 100 different proteins are post-translationally imported into the peroxisomal membrane and matrix, and their functionality must be closely monitored. In this Review, we briefly discuss the import of peroxisomal membrane proteins, and we emphasize an updated view of both classical and alternative peroxisomal matrix protein import pathways. We highlight different quality control pathways that ensure the degradation of dysfunctional peroxisomal proteins. Finally, we compare peroxisomal matrix protein import with other systems that transport folded proteins across membranes, in particular the twin-arginine translocation (Tat) system and the nuclear pore.
Topics: Membrane Proteins; Peroxisomes; Protein Transport; Intracellular Membranes
PubMed: 37552037
DOI: 10.1242/jcs.260999 -
Cell Biochemistry and Biophysics 2000Peroxisome biogenesis disorders (PBDs) contain various clinical phenotypes; Zellweger syndrome (ZS), neonatal adrenoleukodystrophy (NALD), and infantile Refsum disease... (Review)
Review
Peroxisome biogenesis disorders (PBDs) contain various clinical phenotypes; Zellweger syndrome (ZS), neonatal adrenoleukodystrophy (NALD), and infantile Refsum disease (IRD), decreasing in the clinical severity in this order. We found that all IRD cell lines and some NALD lines belonging to several different complementation groups are temperature-sensitive in peroxisome assembly; that is, they lacked catalase-positive peroxisomes at 37 degrees C, but do gain the peroxisomes at 30 degrees C. We identified heterozygous mutations E55K/R119Stop in the PEX2 gene of an IRD patient of complementation group F. The E55K mutation was the direct cause of the temperature-sensitivity because similar phenotypes could be transferred to PEX2-defective CHO cells by transfecting the mutant gene. Thus, temperature-sensitive peroxisome assembly is representative of milder forms of PBDs.
Topics: Humans; Peroxisomal Disorders; Peroxisomes; Temperature
PubMed: 11330043
DOI: 10.1385/cbb:32:1-3:165 -
Journal of Integrative Plant Biology Feb 2023Protein ubiquitination regulates diverse cellular processes in eukaryotic organisms, from growth and development to stress response. Proteins subjected to ubiquitination... (Review)
Review
Protein ubiquitination regulates diverse cellular processes in eukaryotic organisms, from growth and development to stress response. Proteins subjected to ubiquitination can be found in virtually all subcellular locations and organelles, including peroxisomes, single-membrane and highly dynamic organelles ubiquitous in eukaryotes. Peroxisomes contain metabolic functions essential to plants and animals such as lipid catabolism, detoxification of reactive oxygen species (ROS), biosynthesis of vital hormones and cofactors, and photorespiration. Plant peroxisomes possess a complex proteome with functions varying among different tissue types and developmental stages, and during plant response to distinct environmental cues. However, how these diverse functions are regulated at the post-translational level is poorly understood, especially in plants. In this review, we summarized current knowledge of the involvement of protein ubiquitination in peroxisome protein import, remodeling, pexophagy, and metabolism, focusing on plants, and referencing discoveries from other eukaryotic systems when relevant. Based on previous ubiquitinomics studies, we compiled a list of 56 ubiquitinated Arabidopsis peroxisomal proteins whose functions are associated with all the major plant peroxisomal metabolic pathways. This discovery suggests a broad impact of protein ubiquitination on plant peroxisome functions, therefore substantiating the need to investigate this significant regulatory mechanism in peroxisomes at more depths.
Topics: Animals; Peroxisomes; Ubiquitination; Plants; Arabidopsis; Arabidopsis Proteins
PubMed: 35975710
DOI: 10.1111/jipb.13346 -
Biochemical and Biophysical Research... Jan 2016Pexophagy is the selective degradation of peroxisomes for maintaining peroxisome homeostasis within cells. Peroxisome dynamics and pexophagy are important events...
Pexophagy is the selective degradation of peroxisomes for maintaining peroxisome homeostasis within cells. Peroxisome dynamics and pexophagy are important events required to maintain the quality control of peroxisomes, thereby preventing peroxisome-associated diseases. To identify novel pexophagy modulators, we developed a cell-based screening system and selected 2,2'-dipyridyl (2,2-DP) as a candidate molecule. 2,2-DP treatment induced peroxisome degradation as evidenced by an increased number of low-pH autolysosomes originating from peroxisomes and a decrease in the expression of peroxisomal proteins such as catalase, Pex14, and PMP70. The phenotype was defined as pexophagy, because 2,2-DP induced autophagy and inhibition of autophagy significantly reduced the degree of peroxisome degradation. Mechanistically, 2,2-DP-dependent pexophagy seemed to be mediated by iron chelation, since another iron chelator displayed a similar effect on pexophagy, but a copper chelator did not. Notably, iron replenishment prevented 2,2-DP-mediated pexophagy. Taken together, our results suggest that 2,2-DP treatment disrupts peroxisome dynamics and promotes pexophagy through iron depletion.
Topics: 2,2'-Dipyridyl; Autophagy; Cell Line; Dose-Response Relationship, Drug; Humans; Iron Chelating Agents; Peroxisomes; Retinal Pigment Epithelium
PubMed: 26721431
DOI: 10.1016/j.bbrc.2015.12.098