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MBio Aug 2023Peroxisomes are versatile eukaryotic organelles essential for many functions in fungi, including fatty acid metabolism, reactive oxygen species detoxification, and...
Peroxisomes are versatile eukaryotic organelles essential for many functions in fungi, including fatty acid metabolism, reactive oxygen species detoxification, and secondary metabolite biosynthesis. A suite of Pex proteins (peroxins) maintains peroxisomes, while peroxisomal matrix enzymes execute peroxisome functions. Insertional mutagenesis identified peroxin genes as essential components supporting the intraphagosomal growth of the fungal pathogen . Disruption of the peroxins Pex5, Pex10, or Pex33 in prevented peroxisome import of proteins targeted to the organelle via the PTS1 pathway. This loss of peroxisome protein import limited intracellular growth in macrophages and attenuated virulence in an acute histoplasmosis infection model. Interruption of the alternate PTS2 import pathway also attenuated virulence, although only at later time points of infection. The Sid1 and Sid3 siderophore biosynthesis proteins contain a PTS1 peroxisome import signal and localize to the peroxisome. Loss of either the PTS1 or PTS2 peroxisome import pathway impaired siderophore production and iron acquisition in , demonstrating compartmentalization of at least some biosynthetic steps for hydroxamate siderophore biosynthesis. However, the loss of PTS1-based peroxisome import caused earlier virulence attenuation than either the loss of PTS2-based protein import or the loss of siderophore biosynthesis, indicating additional PTS1-dependent peroxisomal functions are important for virulence. Furthermore, disruption of the Pex11 peroxin also attenuated virulence independently of peroxisomal protein import and siderophore biosynthesis. These findings demonstrate peroxisomes contribute to pathogenesis by facilitating siderophore biosynthesis and another unidentified role(s) for the organelle during fungal virulence. IMPORTANCE The fungal pathogen infects host phagocytes and establishes a replication-permissive niche within the cells. To do so, overcomes and subverts antifungal defense mechanisms which include the limitation of essential micronutrients. replication within host cells requires multiple distinct functions of the fungal peroxisome organelle. These peroxisomal functions contribute to pathogenesis at different times during infection and include peroxisome-dependent biosynthesis of iron-scavenging siderophores to enable fungal proliferation, particularly after activation of cell-mediated immunity. The multiple essential roles of fungal peroxisomes reveal this organelle as a potential but untapped target for the development of therapeutics.
Topics: Histoplasma; Virulence; Siderophores; Peroxins; Peroxisomes; Adaptation, Physiological
PubMed: 37432032
DOI: 10.1128/mbio.03284-22 -
PLoS Pathogens Nov 2021Entamoeba histolytica is believed to be devoid of peroxisomes, like most anaerobic protists. In this work, we provided the first evidence that peroxisomes are present in...
Entamoeba histolytica is believed to be devoid of peroxisomes, like most anaerobic protists. In this work, we provided the first evidence that peroxisomes are present in E. histolytica, although only seven proteins responsible for peroxisome biogenesis (peroxins) were identified (Pex1, Pex6, Pex5, Pex11, Pex14, Pex16, and Pex19). Targeting matrix proteins to peroxisomes is reduced to the PTS1-dependent pathway mediated via the soluble Pex5 receptor, while the PTS2 receptor Pex7 is absent. Immunofluorescence microscopy showed that peroxisomal markers (Pex5, Pex14, Pex16, Pex19) are present in vesicles distinct from mitosomes, the endoplasmic reticulum, and the endosome/phagosome system, except Pex11, which has dual localization in peroxisomes and mitosomes. Immunoelectron microscopy revealed that Pex14 localized to vesicles of approximately 90-100 nm in diameter. Proteomic analyses of affinity-purified peroxisomes and in silico PTS1 predictions provided datasets of 655 and 56 peroxisomal candidates, respectively; however, only six proteins were shared by both datasets, including myo-inositol dehydrogenase (myo-IDH). Peroxisomal NAD-dependent myo-IDH appeared to be a dimeric enzyme with high affinity to myo-inositol (Km 0.044 mM) and can utilize also scyllo-inositol, D-glucose and D-xylose as substrates. Phylogenetic analyses revealed that orthologs of myo-IDH with PTS1 are present in E. dispar, E. nutalli and E. moshkovskii but not in E. invadens, and form a monophyletic clade of mostly peroxisomal orthologs with free-living Mastigamoeba balamuthi and Pelomyxa schiedti. The presence of peroxisomes in E. histolytica and other archamoebae breaks the paradigm of peroxisome absence in anaerobes and provides a new potential target for the development of antiparasitic drugs.
Topics: Anaerobiosis; Entamoeba histolytica; Inositol; Mutation; Peroxins; Peroxisomal Targeting Signals; Peroxisomes; Phylogeny; Protozoan Proteins
PubMed: 34780573
DOI: 10.1371/journal.ppat.1010041 -
Biochimica Et Biophysica Acta May 2016Peroxisomes are dynamic organelles that can adjust their size and number in response to cellular demand and environmental stimuli. They can propagate from pre-existing... (Review)
Review
Peroxisomes are dynamic organelles that can adjust their size and number in response to cellular demand and environmental stimuli. They can propagate from pre-existing peroxisomes through growth and division, as well as de novo from the endoplasmic reticulum (ER). However, to what extend that these two distinct peroxisome biogenesis pathways are involved in maintaining peroxisome numbers in cycling cells is unclear. Recent studies in yeast suggest that the ER plays a direct role in the maintenance of peroxisomes. However, the role of the ER in mammalian system is under debate. In this review, we outline the recent progress in understanding the biogenesis of mammalian peroxisomes. We herein discuss some of the discrepancies in the literature and the outstanding questions in the field.
Topics: Animals; Endoplasmic Reticulum; Gene Expression Regulation; Humans; Lipoproteins; Membrane Proteins; Mitochondria; Organelle Biogenesis; Peroxins; Peroxisomes; Protein Isoforms; Protein Structure, Secondary; Protein Structure, Tertiary; Protein Transport; Signal Transduction
PubMed: 26408931
DOI: 10.1016/j.bbamcr.2015.09.026 -
Microscopy Research and Technique Jun 2003Peroxisomes are essential organelles that may be involved in various functions, dependent on organism, cell type, developmental stage of the cell, and the environment.... (Review)
Review
Peroxisomes are essential organelles that may be involved in various functions, dependent on organism, cell type, developmental stage of the cell, and the environment. Until recently, peroxisomes were viewed as a class of static organelles that developed by growth and fission from pre-existing organelles. Recent observations have challenged this view by providing evidence that peroxisomes may be part of the endomembrane system and constitute a highly dynamic population of organelles that arises and is removed upon environmental demands. Additionally, evidence is now accumulating that peroxisomes may arise by alternative methods. This review summarizes relevant recent data on this subject. In addition, the progress in the understanding of the principles of the peroxisomal matrix protein import machinery is discussed.
Topics: PHEX Phosphate Regulating Neutral Endopeptidase; Peroxisomes; Proteins; Yeasts
PubMed: 12740820
DOI: 10.1002/jemt.10323 -
MBio May 2020Peroxisomes are found in essentially all eukaryotic cells and have been described as important hubs in innate sensing and the induction of type III interferons upon...
Peroxisomes are found in essentially all eukaryotic cells and have been described as important hubs in innate sensing and the induction of type III interferons upon viral infection. Nevertheless, it remains poorly investigated how viral pathogens modulate biogenesis or function of peroxisomes to evade innate sensing and restriction. In a recent study, Hobman and colleagues found that the accessory viral protein u (Vpu) of HIV-1 inhibits peroxisome activity by depleting cellular peroxisome pools. This depletion could be ascribed to a Vpu-dependent induction of four microRNAs (miRNAs) that suppress the expression of peroxisomal biogenesis factors PEX2, PEX7, PEX11B, and PEX13. Although the downstream effects on antiretroviral gene expression and HIV-1 replication remain to be determined, these findings provide important insights into peroxisome biogenesis and the modulation of cell organelles by HIV-1 Vpu.
Topics: HIV Seropositivity; HIV-1; Human Immunodeficiency Virus Proteins; Humans; Peroxisomes; Viral Regulatory and Accessory Proteins
PubMed: 32457250
DOI: 10.1128/mBio.00967-20 -
Molecular Cell Jun 2022Metabolism is emerging as a central influencer of multiple disease states in humans. Peroxisomes are central metabolic organelles whose decreased function gives rise to... (Review)
Review
Metabolism is emerging as a central influencer of multiple disease states in humans. Peroxisomes are central metabolic organelles whose decreased function gives rise to severe peroxisomal diseases. Recently, it is becoming clear that, beyond such rare inborn errors, the deterioration of peroxisomal functions contributes to multiple and prevalent diseases such as cancer, viral infection, diabetes, and neurodegeneration. Despite the clear importance of peroxisomes in common pathophysiological processes, research on the mechanisms underlying their contributions is still sparse. Here, we highlight the timeliness of focusing on peroxisomes in current research on central, abundant, and society-impacting human pathologies. As peroxisomes are now coming into the spotlight, it is clear that intensive research into these important organelles will enable a better understanding of their contribution to human health, serving as the basis to develop new diagnostic and therapeutic approaches to prevent and treat human diseases.
Topics: Humans; Peroxisomal Disorders; Peroxisomes
PubMed: 35714584
DOI: 10.1016/j.molcel.2022.05.028 -
The Plant Journal : For Cell and... Jul 2022Peroxisomes are universal eukaryotic organelles essential to plants and animals. Most peroxisomal matrix proteins carry peroxisome targeting signal type 1 (PTS1), a...
Peroxisomes are universal eukaryotic organelles essential to plants and animals. Most peroxisomal matrix proteins carry peroxisome targeting signal type 1 (PTS1), a C-terminal tripeptide. Studies from various kingdoms have revealed influences from sequence upstream of the tripeptide on peroxisome targeting, supporting the view that positive charges in the upstream region are the major enhancing elements. However, a systematic approach to better define the upstream elements influencing PTS1 targeting capability is needed. Here, we used protein sequences from 177 plant genomes to perform large-scale and in-depth analysis of the PTS1 domain, which includes the PTS1 tripeptide and upstream sequence elements. We identified and verified 12 low-frequency PTS1 tripeptides and revealed upstream enhancing and inhibiting sequence patterns for peroxisome targeting, which were subsequently validated in vivo. Follow-up analysis revealed that nonpolar and acidic residues have relatively strong enhancing and inhibiting effects, respectively, on peroxisome targeting. However, in contrast to the previous understanding, positive charges alone do not show the anticipated enhancing effect and that both the position and property of the residues within these patterns are important for peroxisome targeting. We further demonstrated that the three residues immediately upstream of the tripeptide are the core influencers, with a 'basic-nonpolar-basic' pattern serving as a strong and universal enhancing pattern for peroxisome targeting. These findings have significantly advanced our knowledge of the PTS1 domain in plants and likely other eukaryotic species as well. The principles and strategies employed in the present study may also be applied to deciphering auxiliary targeting signals for other organelles.
Topics: Amino Acid Sequence; Animals; Peroxisomal Targeting Signals; Peroxisomes; Plants; Protein Sorting Signals
PubMed: 35603488
DOI: 10.1111/tpj.15840 -
Biochimica Et Biophysica Acta Sep 2012The peroxisome is functionally integrated into an exquisitely complex network of communicating endomembranes which is only beginning to be appreciated. Despite great... (Review)
Review
The peroxisome is functionally integrated into an exquisitely complex network of communicating endomembranes which is only beginning to be appreciated. Despite great advances in identifying essential components and characterizing molecular mechanisms associated with the organelle's biogenesis and function, there is a large gap in our understanding of how peroxisomes are incorporated into metabolic pathways and subcellular communication networks, how they contribute to cellular aging, and where their influence is manifested on the initiation and progression of degenerative disease. In this review, we summarize recent evidence pointing to the organelle as an important regulator of cellular redox balance with potentially far-reaching effects on cell aging and the genesis of human disease. The roles of the organelle in lipid homeostasis, anaplerotic reactions, and other critical metabolic and biochemical processes are addressed elsewhere in this volume. This article is part of a Special Issue entitled: Metabolic Functions and Biogenesis of Peroxisomes in Health and Disease.
Topics: Animals; Catalase; Cell Transformation, Neoplastic; Cellular Senescence; Fluoresceins; Humans; Longevity; Mitochondria; Ouabain; Peroxisomes; Reactive Oxygen Species
PubMed: 22497955
DOI: 10.1016/j.bbadis.2012.03.013 -
Genetics in Medicine : Official Journal... Nov 2023Zellweger spectrum disorders (ZSDs) are known as autosomal recessive disorders caused by defective peroxisome biogenesis due to bi-allelic pathogenic variants in any of...
PURPOSE
Zellweger spectrum disorders (ZSDs) are known as autosomal recessive disorders caused by defective peroxisome biogenesis due to bi-allelic pathogenic variants in any of at least 13 different PEX genes. Here, we report 2 unrelated patients who present with an autosomal dominant ZSD.
METHODS
We performed biochemical and genetic studies in blood and skin fibroblasts of the patients and demonstrated the pathogenicity of the identified PEX14 variants by functional cell studies.
RESULTS
We identified 2 different single heterozygous de novo variants in the PEX14 genes of 2 patients diagnosed with ZSD. Both variants cause messenger RNA mis-splicing, leading to stable expression of similar C-terminally truncated PEX14 proteins. Functional studies indicated that the truncated PEX14 proteins lost their function in peroxisomal matrix protein import and cause increased degradation of peroxisomes, ie, pexophagy, thus exerting a dominant-negative effect on peroxisome functioning. Inhibition of pexophagy by different autophagy inhibitors or genetic knockdown of the peroxisomal autophagy receptor NBR1 resulted in restoration of peroxisomal functions in the patients' fibroblasts.
CONCLUSION
Our finding of an autosomal dominant ZSD expands the genetic repertoire of ZSDs. Our study underscores that single heterozygous variants should not be ignored as possible genetic cause of diseases with an established autosomal recessive mode of inheritance.
Topics: Humans; Alleles; Peroxisomes; Protein Transport; Proteins; Zellweger Syndrome
PubMed: 37493040
DOI: 10.1016/j.gim.2023.100944 -
IUBMB Life Apr 2001Peroxisomes are one of the main sites in the cell where oxygen free radicals are both generated and scavenged. The balance between these two processes is believed to be... (Review)
Review
Peroxisomes are one of the main sites in the cell where oxygen free radicals are both generated and scavenged. The balance between these two processes is believed to be of great importance for proper functioning of cells and has been implicated in aging and carcinogenesis. We will give an overview of the peroxisomal processes involved in the oxygen radical homeostasis and its implications for the cell.
Topics: Animals; Antioxidants; Free Radical Scavengers; Homeostasis; Humans; Lipid Peroxidation; Models, Biological; Oxidative Stress; Peroxisomes; Reactive Oxygen Species
PubMed: 11569916
DOI: 10.1080/152165401753311762