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Trends in Molecular Medicine Feb 2020Peroxisomes share extensive metabolic connections with other cell organelles. Membrane contact sites (MCSs) establish and maintain such interactions, and they are vital... (Review)
Review
Peroxisomes share extensive metabolic connections with other cell organelles. Membrane contact sites (MCSs) establish and maintain such interactions, and they are vital for organelle positioning and motility. In the past few years peroxisome interactions and MCSs with other cellular organelles have been explored extensively, resulting in the identification of new MCSs, the tethering molecules involved, and their functional characterization. Defective tethering and compartmental communication can lead to pathological conditions that can be termed 'organelle interaction diseases'. We review peroxisome-organelle interactions in mammals and summarize the most recent knowledge of mammalian peroxisomal organelle contacts in health and disease.
Topics: Animals; Humans; Mammals; Organelles; Peroxisomes
PubMed: 31727543
DOI: 10.1016/j.molmed.2019.09.012 -
Methods in Molecular Biology (Clifton,... 2023The importance of peroxisomes in the context of viral infections has been increasingly demonstrated in recent years. The discovery that MAVS localizes at peroxisomes and...
The importance of peroxisomes in the context of viral infections has been increasingly demonstrated in recent years. The discovery that MAVS localizes at peroxisomes and that peroxisomal and mitochondrial MAVS perform complementing functions within the antiviral response has raised the interest in studying the peroxisome-dependent signaling in the context of infection by different viruses. To that end, specific experimental procedures should be applied, taking into consideration the endogenous localization of MAVS at both organelles. The analysis of peroxisomal MAVS activation requires, hence, the preliminar generation and validation of cell lines where MAVS localizes solely at peroxisomes, as well as other specific cellular tools. Here, we present a detailed protocol to analyse the peroxisome-dependent antiviral response, using virus-specific and virus-unspecific stimuli.
Topics: Antiviral Agents; Adaptor Proteins, Signal Transducing; Peroxisomes; Signal Transduction; Mitochondria; Immunity, Innate
PubMed: 36952193
DOI: 10.1007/978-1-0716-3048-8_20 -
Methods in Molecular Biology (Clifton,... 2023Drosophila melanogaster is a proven metazoan model to investigate the fundamentals of human genetic diseases including peroxisome-related disorders. Drosophila have...
Drosophila melanogaster is a proven metazoan model to investigate the fundamentals of human genetic diseases including peroxisome-related disorders. Drosophila have facile cell and animal culture but with a relatively simpler genome and organ morphology compared to vertebrates. Drosophila Schneider 2 (S2) cells have been used extensively as a platform for investigating peroxisome functions like transport along the cytoskeleton via their amenability to RNA-interference (RNAi)-based gene knockdown. Similarly, novel findings regarding tissue-specific roles for peroxisomes have come from studies in developing flies. Individual organs can be targeted for RNAi or gene mutations affecting a limited group of cells in the context of the entire animal. Here, we provide basic protocols on how to visualize peroxisomes and manipulate expression of the Peroxin or other peroxisome genes in S2 cells and developing Drosophila organs.
Topics: Animals; Humans; Drosophila; Drosophila melanogaster; Peroxisomes; Drosophila Proteins; RNA Interference
PubMed: 36952206
DOI: 10.1007/978-1-0716-3048-8_33 -
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 -
Current Genetics Dec 2022Peroxisomes are highly dynamic organelles present in most eukaryotic cells. They also play an important role in human health and the optimum functioning of cells. An... (Review)
Review
Peroxisomes are highly dynamic organelles present in most eukaryotic cells. They also play an important role in human health and the optimum functioning of cells. An extensive repertoire of proteins is associated with the biogenesis and function of these organelles. Two protein families that are involved in regulating peroxisome number in a cell directly or indirectly are Pex11 and Pex30. Interestingly, these proteins are also reported to regulate the contact sites between peroxisomes and other cell organelles such as mitochondria, endoplasmic reticulum and lipid droplets. In this manuscript, we review our current knowledge of the role of these proteins in peroxisome biogenesis in various yeast species. Further, we also discuss in detail the role of these protein families in the regulation of inter-organelle contacts in yeast.
Topics: Humans; Peroxisomes; Saccharomyces cerevisiae Proteins; Membrane Proteins; Peroxins; Endoplasmic Reticulum
PubMed: 36242632
DOI: 10.1007/s00294-022-01254-y -
Methods in Molecular Biology (Clifton,... 2023Computational approaches are practical when investigating putative peroxisomal proteins and for sub-peroxisomal protein localization in unknown protein sequences....
Computational approaches are practical when investigating putative peroxisomal proteins and for sub-peroxisomal protein localization in unknown protein sequences. Nowadays, advancements in computational methods and Machine Learning (ML) can be used to hasten the discovery of novel peroxisomal proteins and can be combined with more established computational methodologies. Here, we explain and list some of the most used tools and methodologies for novel peroxisomal protein detection and localization.
Topics: Peroxisomes; Protein Transport; Amino Acid Sequence; Proteins; Machine Learning
PubMed: 36952202
DOI: 10.1007/978-1-0716-3048-8_29 -
Nature Jul 2022Peroxisomes are ubiquitous organelles that house various metabolic reactions and are essential for human health. Luminal peroxisomal proteins are imported from the...
Peroxisomes are ubiquitous organelles that house various metabolic reactions and are essential for human health. Luminal peroxisomal proteins are imported from the cytosol by mobile receptors, which then recycle back to the cytosol by a poorly understood process. Recycling requires receptor modification by a membrane-embedded ubiquitin ligase complex comprising three RING finger domain-containing proteins (Pex2, Pex10 and Pex12). Here we report a cryo-electron microscopy structure of the ligase complex, which together with biochemical and in vivo experiments reveals its function as a retrotranslocation channel for peroxisomal import receptors. Each subunit of the complex contributes five transmembrane segments that co-assemble into an open channel. The three ring finger domains form a cytosolic tower, with ring finger 2 (RF2) positioned above the channel pore. We propose that the N terminus of a recycling receptor is inserted from the peroxisomal lumen into the pore and monoubiquitylated by RF2 to enable extraction into the cytosol. If recycling is compromised, receptors are polyubiquitylated by the concerted action of RF10 and RF12 and degraded. This polyubiquitylation pathway also maintains the homeostasis of other peroxisomal import factors. Our results clarify a crucial step during peroxisomal protein import and reveal why mutations in the ligase complex cause human disease.
Topics: Cryoelectron Microscopy; Cytosol; Humans; Membrane Proteins; Peroxins; Peroxisomal Biogenesis Factor 2; Peroxisomes; Polyubiquitin; Protein Transport; RING Finger Domains; Receptors, Cytoplasmic and Nuclear; Ubiquitin-Protein Ligase Complexes
PubMed: 35768507
DOI: 10.1038/s41586-022-04903-x -
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 -
Proceedings of the National Academy of... Jan 2020The adaptation of eukaryotic cells to anaerobic conditions is reflected by substantial changes to mitochondrial metabolism and functional reduction. Hydrogenosomes...
The adaptation of eukaryotic cells to anaerobic conditions is reflected by substantial changes to mitochondrial metabolism and functional reduction. Hydrogenosomes belong among the most modified mitochondrial derivative and generate molecular hydrogen concomitant with ATP synthesis. The reduction of mitochondria is frequently associated with loss of peroxisomes, which compartmentalize pathways that generate reactive oxygen species (ROS) and thus protect against cellular damage. The biogenesis and function of peroxisomes are tightly coupled with mitochondria. These organelles share fission machinery components, oxidative metabolism pathways, ROS scavenging activities, and some metabolites. The loss of peroxisomes in eukaryotes with reduced mitochondria is thus not unexpected. Surprisingly, we identified peroxisomes in the anaerobic, hydrogenosome-bearing protist We found a conserved set of peroxin (Pex) proteins that are required for protein import, peroxisomal growth, and division. Key membrane-associated Pexs (Pex3, Pex11, and Pex14) were visualized in numerous vesicles distinct from hydrogenosomes, the endoplasmic reticulum (ER), and Golgi complex. Proteomic analysis of cellular fractions and prediction of peroxisomal targeting signals (PTS1/PTS2) identified 51 putative peroxisomal matrix proteins. Expression of selected proteins in revealed specific targeting to peroxisomes. The matrix proteins identified included components of acyl-CoA and carbohydrate metabolism and pyrimidine and CoA biosynthesis, whereas no components related to either β-oxidation or catalase were present. In conclusion, we identified a subclass of peroxisomes, named "anaerobic" peroxisomes that shift the current paradigm and turn attention to the reductive evolution of peroxisomes in anaerobic organisms.
Topics: Anaerobiosis; Archamoebae; Mitochondria; Oxidation-Reduction; Peroxins; Peroxisomes; Protozoan Proteins; Reactive Oxygen Species
PubMed: 31932444
DOI: 10.1073/pnas.1909755117 -
Life Science Alliance May 2023Peroxisomes are organelles with key roles in metabolism including long-chain fatty acid production. Their metabolic functions overlap and interconnect with those of...
Peroxisomes are organelles with key roles in metabolism including long-chain fatty acid production. Their metabolic functions overlap and interconnect with those of mitochondria, with which they share an overlapping but distinct proteome. Both organelles are degraded by selective autophagy processes termed pexophagy and mitophagy. Although mitophagy has received intense attention, the pathways linked to pexophagy and associated tools are less well developed. We have identified the neddylation inhibitor MLN4924 as a potent activator of pexophagy and show that this is mediated by the HIF1α-dependent up-regulation of BNIP3L/NIX, a known adaptor for mitophagy. We show that this pathway is distinct from pexophagy induced by the USP30 deubiquitylase inhibitor CMPD-39, for which we identify the adaptor NBR1 as a central player. Our work suggests a level of complexity to the regulation of peroxisome turnover that includes the capacity to coordinate with mitophagy, via NIX, which acts as a rheostat for both processes.
Topics: Macroautophagy; Autophagy; Mitophagy; Peroxisomes
PubMed: 36810161
DOI: 10.26508/lsa.202201825