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Biological Chemistry Feb 2023Peroxisomal integrity and function are highly dependent on its membrane and soluble (matrix) components. Matrix enzymes are imported post-translationally in a folded or... (Review)
Review
Peroxisomal integrity and function are highly dependent on its membrane and soluble (matrix) components. Matrix enzymes are imported post-translationally in a folded or even oligomeric state, via a still mysterious protein translocation mechanism. They are guided to peroxisomes via the Peroxisomal Targeting Signal (PTS) sequences which are recognized by specific cytosolic receptors, Pex5, Pex7 and Pex9. Subsequently, cargo-loaded receptors bind to the docking complex in an initial step, followed by channel formation, cargo-release, receptor-recycling and -quality control. The docking complexes of different species share Pex14 as their core component but differ in composition and oligomeric state of Pex14. Here we review and highlight the latest insights on the structure and function of the peroxisomal docking complex. We summarize differences between yeast and mammals and then we integrate this knowledge into our current understanding of the import machinery.
Topics: Animals; Membrane Proteins; Peroxisomes; Protein Transport; Carrier Proteins; Saccharomyces cerevisiae; Mammals
PubMed: 36117327
DOI: 10.1515/hsz-2022-0161 -
Sub-cellular Biochemistry 2018Our knowledge of the proteome of plant peroxisomes is far from being complete, and the functional complexity and plasticity of this cell organelle are amazingly high... (Review)
Review
Our knowledge of the proteome of plant peroxisomes is far from being complete, and the functional complexity and plasticity of this cell organelle are amazingly high particularly in plants, as exemplified by the model species Arabidopsis thaliana. Plant-specific peroxisome functions that have been uncovered only recently include, for instance, the participation of peroxisomes in phylloquinone and biotin biosynthesis. Experimental proteome studies have been proved very successful in defining the proteome of Arabidopsis peroxisomes but this approach also faces significant challenges and limitations. Complementary to experimental approaches, computational methods have emerged as important powerful tools to define the proteome of soluble matrix proteins of plant peroxisomes. Compared to other cell organelles such as mitochondria, plastids and the ER, the simultaneous operation of two major import pathways for soluble proteins in peroxisomes is rather atypical. Novel machine learning prediction approaches have been developed for peroxisome targeting signals type 1 (PTS1) and revealed high sensitivity and specificity, as validated by in vivo subcellular targeting analyses in diverse transient plant expression systems. Accordingly, the algorithms allow the correct prediction of many novel peroxisome-targeted proteins from plant genome sequences and the discovery of additional organelle functions. In contrast, the prediction of PTS2 proteins largely remains restricted to genome searches by conserved patterns contrary to more advanced machine learning methods. Here, we summarize and discuss the capabilities and accuracies of available prediction algorithms for PTS1 and PTS2 carrying proteins.
Topics: Arabidopsis; Arabidopsis Proteins; Genome, Plant; Peroxisomes; Protein Sorting Signals; Protein Transport; Proteome
PubMed: 30378021
DOI: 10.1007/978-981-13-2233-4_5 -
Biological Chemistry May 2017In peroxisomal matrix protein import two processes directly depend on the binding and hydrolysis of ATP, both taking place at the late steps of the peroxisomal import... (Review)
Review
In peroxisomal matrix protein import two processes directly depend on the binding and hydrolysis of ATP, both taking place at the late steps of the peroxisomal import cycle. First, ATP hydrolysis is required to initiate a ubiquitin-transfer cascade to modify the import (co-)receptors. These receptors display a dual localization in the cytosol and at the peroxisomal membrane, whereas only the membrane bound fraction receives the ubiquitin modification. The second ATP-dependent process of the import cycle is carried out by the two AAA+-proteins Pex1p and Pex6p. These ATPases form a heterohexameric complex, which is recruited to the peroxisomal import machinery by the membrane anchor protein Pex15p. The Pex1p/Pex6p complex recognizes the ubiquitinated import receptors, pulls them out of the membrane and releases them into the cytosol. There the deubiquitinated receptors are provided for further rounds of import. ATP binding and hydrolysis are required for Pex1p/Pex6p complex formation and receptor export. In this review, we summarize the current knowledge on the peroxisomal import cascade. In particular, we will focus on the ATP-dependent processes, which are so far best understood in the model organism Saccharomyces cerevisiae.
Topics: Adenosine Triphosphate; Animals; Humans; Peroxisomes; Protein Transport; Saccharomyces cerevisiae Proteins; Ubiquitination
PubMed: 27977397
DOI: 10.1515/hsz-2016-0293 -
Quantitative subcellular reconstruction reveals a lipid mediated inter-organelle biogenesis network.Nature Cell Biology Jan 2024The structures and functions of organelles in cells depend on each other but have not been systematically explored. We established stable knockout cell lines of...
The structures and functions of organelles in cells depend on each other but have not been systematically explored. We established stable knockout cell lines of peroxisomal, Golgi and endoplasmic reticulum genes identified in a whole-genome CRISPR knockout screen for inducers of mitochondrial biogenesis stress, showing that defects in peroxisome, Golgi and endoplasmic reticulum metabolism disrupt mitochondrial structure and function. Our quantitative total-organelle profiling approach for focussed ion beam scanning electron microscopy revealed in unprecedented detail that specific organelle dysfunctions precipitate multi-organelle biogenesis defects, impair mitochondrial morphology and reduce respiration. Multi-omics profiling showed a unified proteome response and global shifts in lipid and glycoprotein homeostasis that are elicited when organelle biogenesis is compromised, and that the resulting mitochondrial dysfunction can be rescued with precursors for ether-glycerophospholipid metabolic pathways. This work defines metabolic and morphological interactions between organelles and how their perturbation can cause disease.
Topics: Organelle Biogenesis; Organelles; Peroxisomes; Golgi Apparatus; Mitochondria; Lipids
PubMed: 38129691
DOI: 10.1038/s41556-023-01297-4 -
Molecular Plant Pathology Jun 2022Several filamentous fungi are ecologically and economically important plant pathogens that infect a broad variety of crops. They cause high annual yield losses and... (Review)
Review
Several filamentous fungi are ecologically and economically important plant pathogens that infect a broad variety of crops. They cause high annual yield losses and contaminate seeds and fruits with mycotoxins. Not only powerful infection structures and detrimental toxins, but also cell organelles, such as peroxisomes, play important roles in plant infection. In this review, we summarize recent research results that revealed novel peroxisomal functions of filamentous fungi and highlight the importance of peroxisomes for infection of host plants. Central for fungal virulence are two primary metabolic pathways, fatty acid β-oxidation and the glyoxylate cycle, both of which are required to produce energy, acetyl-CoA, and carbohydrates. These are ultimately needed for the synthesis of cell wall polymers and for turgor generation in infection structures. Most novel results stem from different routes of secondary metabolism and demonstrate that peroxisomes produce important precursors and house various enzymes needed for toxin production and melanization of appressoria. All these peroxisomal functions in fungal virulence might represent elegant targets for improved crop protection.
Topics: Fungi; Peroxisomes; Plants; Virulence
PubMed: 35001508
DOI: 10.1111/mpp.13180 -
The Biochemical Journal May 2023Mitochondrial β-oxidation is the most prominent pathway for fatty acid oxidation but alternative oxidative metabolism exists. Fatty acid ω-oxidation is one of these... (Review)
Review
Mitochondrial β-oxidation is the most prominent pathway for fatty acid oxidation but alternative oxidative metabolism exists. Fatty acid ω-oxidation is one of these pathways and forms dicarboxylic acids as products. These dicarboxylic acids are metabolized through peroxisomal β-oxidation representing an alternative pathway, which could potentially limit the toxic effects of fatty acid accumulation. Although dicarboxylic acid metabolism is highly active in liver and kidney, its role in physiology has not been explored in depth. In this review, we summarize the biochemical mechanism of the formation and degradation of dicarboxylic acids through ω- and β-oxidation, respectively. We will discuss the role of dicarboxylic acids in different (patho)physiological states with a particular focus on the role of the intermediates and products generated through peroxisomal β-oxidation. This review is expected to increase the understanding of dicarboxylic acid metabolism and spark future research.
Topics: Microbodies; Fatty Acids; Oxidation-Reduction; Mitochondria; Liver; Dicarboxylic Acids
PubMed: 37140888
DOI: 10.1042/BCJ20230041 -
Nature Cell Biology Aug 2017Understanding organelle biogenesis is a central focus of cell biology. Whereas some are generated from existing organelles, others can be generated de novo. Most de novo... (Review)
Review
Understanding organelle biogenesis is a central focus of cell biology. Whereas some are generated from existing organelles, others can be generated de novo. Most de novo organelle biogenesis occurs in the endoplasmic reticulum (ER). Here, we review the role of the ER in the generation of peroxisomes, lipid droplets, and omegasomes, which are platforms for autophagosome production, and discuss how ER subdomains with specific protein and lipid composition form and promote organelle biogenesis.
Topics: Animals; Autophagosomes; Endoplasmic Reticulum; Humans; Intracellular Signaling Peptides and Proteins; Lipid Droplets; Lipid Metabolism; Organelle Biogenesis; Peroxisomes; Signal Transduction
PubMed: 28714972
DOI: 10.1038/ncb3579 -
Physiological Reviews Jan 2018Peroxisomes are highly dynamic intracellular organelles involved in a variety of metabolic functions essential for the metabolism of long-chain fatty acids, d-amino... (Review)
Review
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 (HO). Because of its relatively low reactivity (as a mild oxidant), HO has a comparatively long intracellular half-life and a high diffusion rate, all of which makes HO 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.
Topics: Animals; Homeostasis; Humans; Hydrogen Peroxide; Mitochondria; Peroxisomes; Proteostasis; Reactive Oxygen Species
PubMed: 29167332
DOI: 10.1152/physrev.00033.2016 -
Current Opinion in Microbiology Dec 2014Peroxisomes are ubiquitous organelles that harbor diverse metabolic pathways, which are essential for normal cell performance. Conserved functions of these organelles... (Review)
Review
Peroxisomes are ubiquitous organelles that harbor diverse metabolic pathways, which are essential for normal cell performance. Conserved functions of these organelles are hydrogen peroxide metabolism and β-oxidation. Cells employ multiple quality control mechanisms to ensure proper peroxisome function and to protect peroxisomes from damage. These involve the function of molecular chaperones, a peroxisomal Lon protease and autophagic removal of dysfunctional organelles. In addition, multiple mechanisms exist to combat peroxisomal oxidative stress. Here, we outline recent advances in our understanding of peroxisomal quality control, focussing on yeast and filamentous fungi.
Topics: Oxidation-Reduction; Peroxisomes; Protein Processing, Post-Translational; Signal Transduction
PubMed: 25305535
DOI: 10.1016/j.mib.2014.09.009 -
Nature Communications Nov 2023Ubiquitination is a post-translational modification initiated by the E1 enzyme UBA1, which transfers ubiquitin to ~35 E2 ubiquitin-conjugating enzymes. While UBA1 loss...
Ubiquitination is a post-translational modification initiated by the E1 enzyme UBA1, which transfers ubiquitin to ~35 E2 ubiquitin-conjugating enzymes. While UBA1 loss is cell lethal, it remains unknown how partial reduction in UBA1 activity is endured. Here, we utilize deep-coverage mass spectrometry to define the E1-E2 interactome and to determine the proteins that are modulated by knockdown of UBA1 and of each E2 in human cells. These analyses define the UBA1/E2-sensitive proteome and the E2 specificity in protein modulation. Interestingly, profound adaptations in peroxisomes and other organelles are triggered by decreased ubiquitination. While the cargo receptor PEX5 depends on its mono-ubiquitination for binding to peroxisomal proteins and importing them into peroxisomes, we find that UBA1/E2 knockdown induces the compensatory upregulation of other PEX proteins necessary for PEX5 docking to the peroxisomal membrane. Altogether, this study defines a homeostatic mechanism that sustains peroxisomal protein import in cells with decreased ubiquitination capacity.
Topics: Humans; Ubiquitination; Ubiquitin; Protein Transport; Peroxisomes; Intracellular Membranes
PubMed: 37963875
DOI: 10.1038/s41467-023-43262-7