-
Essays in Biochemistry Aug 2022Plant peroxisomes host critical metabolic reactions and insulate the rest of the cell from reactive byproducts. The specialization of peroxisomal reactions is rooted in... (Review)
Review
Plant peroxisomes host critical metabolic reactions and insulate the rest of the cell from reactive byproducts. The specialization of peroxisomal reactions is rooted in how the organelle modulates its proteome to be suitable for the tissue, environment, and developmental stage of the organism. The story of plant peroxisomal proteostasis begins with transcriptional regulation of peroxisomal protein genes and the synthesis, trafficking, import, and folding of peroxisomal proteins. The saga continues with assembly and disaggregation by chaperones and degradation via proteases or the proteasome. The story concludes with organelle recycling via autophagy. Some of these processes as well as the proteins that facilitate them are peroxisome-specific, while others are shared among organelles. Our understanding of translational regulation of plant peroxisomal protein transcripts and proteins necessary for pexophagy remain based in findings from other models. Recent strides to elucidate transcriptional control, membrane dynamics, protein trafficking, and conditions that induce peroxisome turnover have expanded our knowledge of plant peroxisomal proteostasis. Here we review our current understanding of the processes and proteins necessary for plant peroxisome proteostasis-the emergence, maintenance, and clearance of the peroxisomal proteome.
Topics: Autophagy; Peroxisomes; Protein Transport; Proteome; Proteostasis
PubMed: 35538741
DOI: 10.1042/EBC20210059 -
The Journal of Cell Biology May 2021The VPS13 gene family consists of VPS13A-D in mammals. Although all four genes have been linked to human diseases, their cellular functions are poorly understood,...
The VPS13 gene family consists of VPS13A-D in mammals. Although all four genes have been linked to human diseases, their cellular functions are poorly understood, particularly those of VPS13D. We generated and characterized knockouts of each VPS13 gene in HeLa cells. Among the individual knockouts, only VPS13D-KO cells exhibit abnormal mitochondrial morphology. Additionally, VPS13D loss leads to either partial or complete peroxisome loss in several transformed cell lines and in fibroblasts derived from a VPS13D mutation-carrying patient with recessive spinocerebellar ataxia. Our data show that VPS13D regulates peroxisome biogenesis.
Topics: HEK293 Cells; HeLa Cells; Humans; Mitochondria; Mutation; Peroxisomes; Proteins
PubMed: 33891012
DOI: 10.1083/jcb.202001188 -
Methods in Molecular Biology (Clifton,... 2017The peroxisomal disorders (PDs) are a heterogeneous group of genetic diseases in man caused by an impairment in peroxisome biogenesis or one of the metabolic functions... (Review)
Review
The peroxisomal disorders (PDs) are a heterogeneous group of genetic diseases in man caused by an impairment in peroxisome biogenesis or one of the metabolic functions of peroxisomes. Thanks to the revolutionary technical developments in gene sequencing methods and their increased use in patient diagnosis, the field of genetic diseases in general and peroxisomal disorders in particular has dramatically changed in the last few years. Indeed, several novel peroxisomal disorders have been identified recently and in addition it has been realized that the phenotypic spectrum of patients affected by a PD keeps widening, which makes clinical recognition of peroxisomal patients increasingly difficult. Here, we describe these new developments and provide guidelines for the clinical and laboratory diagnosis of peroxisomal patients.
Topics: Acyl-CoA Oxidase; Genetic Testing; Humans; Peroxisomal Disorders; Peroxisomal Multifunctional Protein-2; Peroxisomes; Phenotype
PubMed: 28409475
DOI: 10.1007/978-1-4939-6937-1_30 -
Biochimica Et Biophysica Acta May 2016Peroxisome number and quality are maintained by its biogenesis and turnover and are important for the homeostasis of peroxisomes. Peroxisomes are increased in number by... (Review)
Review
Peroxisome number and quality are maintained by its biogenesis and turnover and are important for the homeostasis of peroxisomes. Peroxisomes are increased in number by division with dynamic morphological changes including elongation, constriction, and fission. In the course of peroxisomal division, peroxisomal morphogenesis is orchestrated by Pex11β, dynamin-like protein 1 (DLP1), and mitochondrial fission factor (Mff). Conversely, peroxisome number is reduced by its degradation. Peroxisomes are mainly degraded by pexophagy, a type of autophagy specific for peroxisomes. Upon pexophagy, an adaptor protein translocates on peroxisomal membrane and connects peroxisomes to autophagic machineries. Molecular mechanisms of pexophagy are well studied in yeast systems where several specific adaptor proteins are identified. Pexophagy in mammals also proceeds in a manner dependent on adaptor proteins. In this review, we address the recent progress in studies on peroxisome morphogenesis and pexophagy.
Topics: Animals; Dynamins; Endoplasmic Reticulum; Eukaryotic Cells; GTP Phosphohydrolases; Gene Expression Regulation; Humans; Membrane Proteins; Microtubule-Associated Proteins; Mitochondrial Proteins; Peroxins; Peroxisomes; Protein Isoforms; Protein Structure, Tertiary; Proteolysis; Saccharomyces cerevisiae Proteins; Signal Transduction; Species Specificity; Ubiquitin; Yeasts
PubMed: 26434997
DOI: 10.1016/j.bbamcr.2015.09.032 -
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 -
The Protein Journal Jun 2019Blobel and coworkers discovered in 1978 that peroxisomal proteins are synthesized on free ribosomes in the cytosol and thus provided the grounds for the conception of... (Review)
Review
Blobel and coworkers discovered in 1978 that peroxisomal proteins are synthesized on free ribosomes in the cytosol and thus provided the grounds for the conception of peroxisomes as self-containing organelles. Peroxisomes are highly adaptive and versatile organelles carrying out a wide variety of metabolic functions. A striking feature of the peroxisomal import machinery is that proteins can traverse the peroxisomal membrane in a folded and even oligomeric state via cycling receptors. We outline essential steps of peroxisomal matrix protein import, from targeting of the proteins to the peroxisomal membrane, their translocation via transient pores and export of the corresponding cycling import receptors with emphasis on the situation in yeast. Peroxisomes can contribute to the adaptation of cells to different environmental conditions. This is realized by changes in metabolic functions and thus the enzyme composition of the organelles is adopted according to the cellular needs. In recent years, it turned out that this organellar diversity is based on an elaborate regulation of gene expression and peroxisomal protein import. The latter is in the focus of this review that summarizes our knowledge on the composition and function of the peroxisomal protein import machinery with emphasis on novel alternative protein import pathways.
Topics: Intracellular Membranes; Membrane Proteins; Peroxisomes; Protein Transport; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Ubiquitination
PubMed: 31054036
DOI: 10.1007/s10930-019-09835-6 -
FEMS Yeast Research Jun 2016Peroxisomes are ubiquitous organelles found in most eukaryotic cells. In yeasts, peroxisomes play important roles in cell metabolism, especially in different catabolic... (Review)
Review
Peroxisomes are ubiquitous organelles found in most eukaryotic cells. In yeasts, peroxisomes play important roles in cell metabolism, especially in different catabolic processes including fatty acid β-oxidation, the glyoxylic shunt and methanol metabolism, as well as some biosynthetic processes. In addition, peroxisomes are the compartment in which oxidases and catalase are localized. New peroxisomes mainly arise by fission of pre-existing ones, although they can also be formed from the endoplasmic reticulum (ER). Peroxisomes consist of matrix-soluble proteins and membrane proteins known as peroxins. A total of 34 PEX peroxin genes and proteins have been identified to date. and their functions have been elucidated. Protein import into peroxisomes depends on peroxins and requires specific signals in the structure of transported proteins: PTS1, PTS2 and mPTS. The mechanisms of metabolite penetration into peroxisomes are still poorly understood. Peroxisome number and the volume occupied by these organelles are tightly regulated. Methanol, fatty acids and methylamine act as efficient peroxisome proliferators, whereas glucose and ethanol induce peroxisome autophagic degradation (pexophagy). To date, 42 Atg proteins involved in pexophagy are known. Catabolism and alcoholic fermentation of the major pentose sugar, xylose, depend on peroxisomal enzymes. Overexpression of peroxisomal transketolase and transaldolase activates xylose fermentation. Peroxisomes could be useful as target organelles for overexpression of foreign toxic proteins.
Topics: Biotechnology; Industrial Microbiology; Peroxisomes; Saccharomyces cerevisiae
PubMed: 27189367
DOI: 10.1093/femsyr/fow038 -
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