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Molecular Cell Sep 2022Peroxisomes are ubiquitous organelles whose dysfunction causes fatal human diseases. Most peroxisomal enzymes are imported from the cytosol by the receptor PEX5, which...
Peroxisomes are ubiquitous organelles whose dysfunction causes fatal human diseases. Most peroxisomal enzymes are imported from the cytosol by the receptor PEX5, which interacts with a docking complex in the peroxisomal membrane and then returns to the cytosol after monoubiquitination by a membrane-embedded ubiquitin ligase. The mechanism by which PEX5 shuttles between cytosol and peroxisomes and releases cargo inside the lumen is unclear. Here, we use Xenopus egg extract to demonstrate that PEX5 accompanies cargo completely into the lumen, utilizing WxxxF/Y motifs near its N terminus that bind a lumenal domain of the docking complex. PEX5 recycling is initiated by an amphipathic helix that binds to the lumenal side of the ubiquitin ligase. The N terminus then emerges in the cytosol for monoubiquitination. Finally, PEX5 is extracted from the lumen, resulting in the unfolding of the receptor and cargo release. Our results reveal the unique mechanism by which PEX5 ferries proteins into peroxisomes.
Topics: Carrier Proteins; Humans; Ligases; Peroxisome-Targeting Signal 1 Receptor; Peroxisomes; Protein Transport; Receptors, Cytoplasmic and Nuclear; Ubiquitin
PubMed: 35931083
DOI: 10.1016/j.molcel.2022.07.004 -
Biochimica Et Biophysica Acta May 2016Peroxisomes are distinct membrane-enclosed organelles involved in the β-oxidation of fatty acids and synthesis of ether phospholipids (e.g. plasmalogens), as well as... (Review)
Review
Peroxisomes are distinct membrane-enclosed organelles involved in the β-oxidation of fatty acids and synthesis of ether phospholipids (e.g. plasmalogens), as well as cholesterol and its derivatives (e.g. bile acids). Peroxisomes comprise a distinct and highly segregated subset of cellular proteins, including those of the peroxisome membrane and the interior matrix, and while the mechanisms of protein import into peroxisomes have been extensively studied, they are not fully understood. Here we will examine the potential role of RNA trafficking and localized translation on protein import into peroxisomes and its role in peroxisome biogenesis and function. Given that RNAs encoding peroxisome biogenesis (PEX) and matrix proteins have been found in association with the endoplasmic reticulum and peroxisomes, it suggests that localized translation may play a significant role in the import pathways of these different peroxisomal constituents.
Topics: Animals; Biological Transport; Endoplasmic Reticulum; Eukaryotic Cells; Gene Expression Regulation; Humans; Membrane Proteins; Mutation; Organelle Biogenesis; Peroxisomes; Plants; Protein Isoforms; Protein Sorting Signals; RNA, Messenger; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Signal Transduction
PubMed: 26367800
DOI: 10.1016/j.bbamcr.2015.09.007 -
Cells Sep 2022Although autophagy regulates the quality and quantity of cellular compartments, the regulatory mechanisms underlying peroxisomal autophagy (pexophagy) remain largely...
Although autophagy regulates the quality and quantity of cellular compartments, the regulatory mechanisms underlying peroxisomal autophagy (pexophagy) remain largely unknown. In this study, we identified several BRD4 inhibitors, including molibresib, a novel pexophagy inducer, via chemical library screening. Treatment with molibresib promotes loss of peroxisomes selectively, but not mitochondria, ER, or Golgi apparatus in HeLa cells. Consistently, depletion of BRD4 expression also induced pexophagy in RPE cells. In addition, the inhibition of BRD4 by molibresib increased autophagic degradation of peroxisome ATG7-dependency. We further found that molibresib produced reactive oxygen species (ROS), which potentiates ATM activation. Inhibition of ROS or ATM suppressed the loss of peroxisomes in molibresib-treated cells. Taken together, our data suggest that inhibition of BRD4 promotes pexophagy by increasing ROS and ATM activation.
Topics: Ataxia Telangiectasia Mutated Proteins; Cell Cycle Proteins; HeLa Cells; Humans; Macroautophagy; Nuclear Proteins; Peroxisomes; Reactive Oxygen Species; Transcription Factors
PubMed: 36139416
DOI: 10.3390/cells11182839 -
Cell Cycle (Georgetown, Tex.) 2017Peroxisomes are essential and dynamic organelles that allow cells to rapidly adapt and cope with changing environments and/or physiological conditions by modulation of... (Review)
Review
Peroxisomes are essential and dynamic organelles that allow cells to rapidly adapt and cope with changing environments and/or physiological conditions by modulation of both peroxisome biogenesis and turnover. Peroxisome biogenesis involves the assembly of peroxisome membranes and the import of peroxisomal matrix proteins. The latter depends on the receptor, PEX5, which recognizes peroxisomal matrix proteins in the cytosol directly or indirectly, and transports them to the peroxisomal lumen. In this review, we discuss the role of PEX5 ubiquitination in both peroxisome biogenesis and turnover, specifically in PEX5 receptor recycling, stability and abundance, as well as its role in pexophagy (autophagic degradation of peroxisomes).
Topics: Animals; Autophagy; Homeostasis; Humans; Peroxisome-Targeting Signal 1 Receptor; Peroxisomes; Receptors, Cytoplasmic and Nuclear; Ubiquitination
PubMed: 28933989
DOI: 10.1080/15384101.2017.1376149 -
International Journal of Molecular... Sep 2022Peroxisomes are a class of simple organelles that play an important role in plant reactive oxygen species (ROS) metabolism. Experimental evidence reveals the involvement... (Review)
Review
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.
Topics: Apoptosis; Metabolic Networks and Pathways; Peroxisomes; Plants; Reactive Oxygen Species
PubMed: 36077484
DOI: 10.3390/ijms231710087 -
Cells Jun 2022Peroxisomes are highly dynamic and responsive organelles, which can adjust their morphology, number, intracellular position, and metabolic functions according to... (Review)
Review
Peroxisomes are highly dynamic and responsive organelles, which can adjust their morphology, number, intracellular position, and metabolic functions according to cellular needs. Peroxisome multiplication in mammalian cells involves the concerted action of the membrane-shaping protein PEX11β and division proteins, such as the membrane adaptors FIS1 and MFF, which recruit the fission GTPase DRP1 to the peroxisomal membrane. The latter proteins are also involved in mitochondrial division. Patients with loss of DRP1, MFF or PEX11β function have been identified, showing abnormalities in peroxisomal (and, for the shared proteins, mitochondrial) dynamics as well as developmental and neurological defects, whereas the metabolic functions of the organelles are often unaffected. Here, we provide a timely update on peroxisomal membrane dynamics with a particular focus on peroxisome formation by membrane growth and division. We address the function of PEX11β in these processes, as well as the role of peroxisome-ER contacts in lipid transfer for peroxisomal membrane expansion. Furthermore, we summarize the clinical phenotypes and pathophysiology of patients with defects in the key division proteins DRP1, MFF, and PEX11β as well as in the peroxisome-ER tether ACBD5. Potential therapeutic strategies for these rare disorders with limited treatment options are discussed.
Topics: Animals; GTP Phosphohydrolases; Humans; Mammals; Membrane Proteins; Mitochondria; Mitochondrial Dynamics; Mitochondrial Proteins; Peroxisomes
PubMed: 35741050
DOI: 10.3390/cells11121922 -
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 -
Redox Biology Jun 2019Peroxisomes are ubiquitous cellular organelles required for specific pathways of fatty acid oxidation and lipid synthesis, and until recently their functions in... (Review)
Review
Peroxisomes are ubiquitous cellular organelles required for specific pathways of fatty acid oxidation and lipid synthesis, and until recently their functions in adipocytes have not been well appreciated. Importantly, peroxisomes host many oxygen-consumption reactions and play a major role in generation and detoxification of reactive oxygen species (ROS) and reactive nitrogen species (RNS), influencing whole cell redox status. Here, we review recent progress in peroxisomal functions in lipid metabolism as related to ROS/RNS metabolism and discuss the roles of peroxisomal redox homeostasis in adipogenesis and adipocyte metabolism. We provide a framework for understanding redox regulation of peroxisomal functions in adipocytes together with testable hypotheses for developing therapies for obesity and the related metabolic diseases.
Topics: Adipocytes; Adipogenesis; Energy Metabolism; Homeostasis; Lipid Metabolism; Metabolic Networks and Pathways; Mitochondria; Models, Biological; Oxidation-Reduction; Peroxisomes; Reactive Oxygen Species; Signal Transduction
PubMed: 30921635
DOI: 10.1016/j.redox.2019.101167 -
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 -
Cells Jun 2022The AAA-ATPases Pex1 and Pex6 are required for the formation and maintenance of peroxisomes, membrane-bound organelles that harbor enzymes for specialized metabolism.... (Review)
Review
The AAA-ATPases Pex1 and Pex6 are required for the formation and maintenance of peroxisomes, membrane-bound organelles that harbor enzymes for specialized metabolism. Together, Pex1 and Pex6 form a heterohexameric AAA-ATPase capable of unfolding substrate proteins via processive threading through a central pore. Here, we review the proposed roles for Pex1/Pex6 in peroxisome biogenesis and degradation, discussing how the unfolding of potential substrates contributes to peroxisome homeostasis. We also consider how advances in cryo-EM, computational structure prediction, and mechanisms of related ATPases are improving our understanding of how Pex1/Pex6 converts ATP hydrolysis into mechanical force. Since mutations in and cause the majority of known cases of peroxisome biogenesis disorders such as Zellweger syndrome, insights into Pex1/Pex6 structure and function are important for understanding peroxisomes in human health and disease.
Topics: ATPases Associated with Diverse Cellular Activities; Adenosine Triphosphatases; Homeostasis; Humans; Membrane Proteins; Peroxisomes
PubMed: 35805150
DOI: 10.3390/cells11132067