scholarly journals The Peroxisomal PTS1-Import Defect of PEX1- Deficient Cells Is Independent of Pexophagy in Saccharomyces cerevisiae

2020 ◽  
Vol 21 (3) ◽  
pp. 867 ◽  
Author(s):  
Thomas Mastalski ◽  
Rebecca Brinkmeier ◽  
Harald W. Platta
Keyword(s):  
Autosomal Recessive ◽  
Matrix Protein ◽  
Protein Import ◽  
Beta Oxidation ◽  
Working Models ◽  
Peroxisomal Biogenesis ◽  
Physiologic Role ◽  
Peroxisomal Biogenesis Disorders ◽  
Peroxisomal Function

The important physiologic role of peroxisomes is shown by the occurrence of peroxisomal biogenesis disorders (PBDs) in humans. This spectrum of autosomal recessive metabolic disorders is characterized by defective peroxisome assembly and impaired peroxisomal functions. PBDs are caused by mutations in the peroxisomal biogenesis factors, which are required for the correct compartmentalization of peroxisomal matrix enzymes. Recent work from patient cells that contain the Pex1(G843D) point mutant suggested that the inhibition of the lysosome, and therefore the block of pexophagy, was beneficial for peroxisomal function. The resulting working model proposed that Pex1 may not be essential for matrix protein import at all, but rather for the prevention of pexophagy. Thus, the observed matrix protein import defect would not be caused by a lack of Pex1 activity, but rather by enhanced removal of peroxisomal membranes via pexophagy. In the present study, we can show that the specific block of PEX1 deletion-induced pexophagy does not restore peroxisomal matrix protein import or the peroxisomal function in beta-oxidation in yeast. Therefore, we conclude that Pex1 is directly and essentially involved in peroxisomal matrix protein import, and that the PEX1 deletion-induced pexophagy is not responsible for the defect in peroxisomal function. In order to point out the conserved mechanism, we discuss our findings in the context of the working models of peroxisomal biogenesis and pexophagy in yeasts and mammals.

scholarly journals TRIM37, a novel E3 ligase for PEX5-mediated peroxisomal matrix protein import

2017 ◽  
Vol 216 (9) ◽  
pp. 2843-2858 ◽  
Author(s):  
Wei Wang ◽  
Zhi-Jie Xia ◽  
Jean-Claude Farré ◽  
Suresh Subramani
Keyword(s):  
Oxidative Stress ◽  
Amino Acids ◽  
Matrix Protein ◽  
Protein Import ◽  
Gene Mutations ◽  
Mulibrey Nanism ◽  
Peroxisomal Biogenesis ◽  
Peroxisomal Targeting ◽  
Targeting Signals ◽  
Peroxisomal Biogenesis Disorders

Most proteins destined for the peroxisomal matrix depend on the peroxisomal targeting signals (PTSs), which require the PTS receptor PEX5, whose deficiency causes fatal human peroxisomal biogenesis disorders (PBDs). TRIM37 gene mutations cause muscle–liver–brain–eye (mulibrey) nanism. We found that TRIM37 localizes in peroxisomal membranes and ubiquitylates PEX5 at K464 by interacting with its C-terminal 51 amino acids (CT51), which is required for PTS protein import. PEX5 mutations (K464A or ΔCT51), or TRIM37 depletion or mutation, reduce PEX5 abundance by promoting its proteasomal degradation, thereby impairing its functions in cargo binding and PTS protein import in human cells. TRIM37 or PEX5 depletion induces apoptosis and enhances sensitivity to oxidative stress, underscoring the cellular requirement for functional peroxisomes. Therefore, TRIM37-mediated ubiquitylation stabilizes PEX5 and promotes peroxisomal matrix protein import, suggesting that mulibrey nanism is a new PBD.

scholarly journals Msp1/ATAD1 restores mitochondrial function in Zellweger Spectrum Disease

2020 ◽  
Author(s):  
Esther Nuebel ◽  
Jeffrey T Morgan ◽  
Sarah Fogarty ◽  
Jacob M Winter ◽  
Sandra Lettlova ◽  
...  
Keyword(s):  
Quality Control ◽  
Mitochondrial Function ◽  
Protein Import ◽  
Model Systems ◽  
Translational Efficiency ◽  
Aaa Atpase ◽  
Peroxisomal Biogenesis ◽  
Inherited Metabolic Disorders ◽  
Atp Generation ◽  
Peroxisomal Biogenesis Disorders

Peroxisomal Biogenesis Disorders (PBDs) are a class of inherited metabolic disorders with profound neurological and other phenotypes. The most severe PBDs are caused by mutations in peroxin genes, which result in nonfunctional peroxisomes typically through impaired protein import. In order to better understand the molecular causes of Zellweger Spectrum Disease (ZSD) - the most severe PBDs -, we investigated the fate of peroxisomal mRNAs and proteins in ZSD model systems. We found that loss of peroxisomal import has no effect on peroxin mRNA expression or translational efficiency. Instead, peroxin proteins -still produced at high levels- aberrantly accumulate on the mitochondrial membrane, impairing respiration and ATP generation. Finally, we rescued mitochondrial function in fibroblasts derived from human patients with ZSD by overexpressing ATAD1, an AAA-ATPase that functions in mitochondrial quality control. These findings might provide a new focus of PBD therapies in supporting quality control pathways that protect mitochondrial function.

scholarly journals Reevaluation of the role of Pex1 and dynamin-related proteins in peroxisome membrane biogenesis

2015 ◽  
Vol 211 (5) ◽  
pp. 1041-1056 ◽  
Author(s):  
Alison M. Motley ◽  
Paul C. Galvin ◽  
Lakhan Ekal ◽  
James M. Nuttall ◽  
Ewald H. Hettema
Keyword(s):  
Protein Delivery ◽  
Matrix Protein ◽  
Protein Import ◽  
De Novo ◽  
Primary Role ◽  
Peroxisome Biogenesis ◽  
Peroxisomal Membrane ◽  
Related Proteins ◽  
Peroxisome Membrane

A recent model for peroxisome biogenesis postulates that peroxisomes form de novo continuously in wild-type cells by heterotypic fusion of endoplasmic reticulum–derived vesicles containing distinct sets of peroxisomal membrane proteins. This model proposes a role in vesicle fusion for the Pex1/Pex6 complex, which has an established role in matrix protein import. The growth and division model proposes that peroxisomes derive from existing peroxisomes. We tested these models by reexamining the role of Pex1/Pex6 and dynamin-related proteins in peroxisome biogenesis. We found that induced depletion of Pex1 blocks the import of matrix proteins but does not affect membrane protein delivery to peroxisomes; markers for the previously reported distinct vesicles colocalize in pex1 and pex6 cells; peroxisomes undergo continued growth if fission is blocked. Our data are compatible with the established primary role of the Pex1/Pex6 complex in matrix protein import and show that peroxisomes in Saccharomyces cerevisiae multiply mainly by growth and division.

scholarly journals Zellweger syndrome: Depiction of MRI findings in early infancy at 3.0 Tesla

2017 ◽  
Vol 30 (5) ◽  
pp. 442-444 ◽  
Author(s):  
Cory M Pfeifer ◽  
Carlos A Martinot
Keyword(s):  
Neuronal Migration ◽  
Autosomal Recessive ◽  
Zellweger Syndrome ◽  
Severe Form ◽  
Mri Findings ◽  
3.0 Tesla ◽  
Peroxisomal Biogenesis ◽  
Patient At Risk ◽  
Rare Autosomal Recessive Disease ◽  
Peroxisomal Biogenesis Disorders

Zellweger syndrome, also referred to as cerebrohepatorenal syndrome, is a rare autosomal recessive disease representing the most severe form of the peroxisomal biogenesis disorders. Neuroanatomical sequelae include impaired neuronal migration, diffuse hypomyelination, and sensorineural degeneration. Due to the rare and severe nature of this disorder, early mortality, and comorbidities that place the patient at risk for sedated imaging, high-resolution magnetic resonance imaging findings of Zellweger syndrome are scarce in the literature. Presented here is a case of this rare disease imaged at 3.0 Tesla.

scholarly journals Edgetic Perturbations Contribute to Phenotypic Variability in PEX26 Deficiency

2021 ◽  
Vol 12 ◽  
Author(s):  
Amelie S. Lotz-Havla ◽  
Mathias Woidy ◽  
Philipp Guder ◽  
Jessica Schmiesing ◽  
Ralf Erdmann ◽  
...  
Keyword(s):  
Protein Interaction ◽  
Protein Interactions ◽  
Matrix Protein ◽  
Protein Import ◽  
Phenotypic Variability ◽  
Interaction Network ◽  
Underlying Disease ◽  
Protein Protein Interactions ◽  
Peroxisomal Disorders ◽  
Peroxisomal Biogenesis

Peroxisomes share metabolic pathways with other organelles and peroxisomes are embedded into key cellular processes. However, the specific function of many peroxisomal proteins remains unclear and restricted knowledge of the peroxisomal protein interaction network limits a precise mapping of this network into the cellular metabolism. Inborn peroxisomal disorders are autosomal or X-linked recessive diseases that affect peroxisomal biogenesis (PBD) and/or peroxisomal metabolism. Pathogenic variants in the PEX26 gene lead to peroxisomal disorders of the full Zellweger spectrum continuum. To investigate the phenotypic complexity of PEX26 deficiency, we performed a combined organelle protein interaction screen and network medicine approach and 1) analyzed whether PEX26 establishes interactions with other peroxisomal proteins, 2) deciphered the PEX26 interaction network, 3) determined how PEX26 is involved in further processes of peroxisomal biogenesis and metabolism, and 4) showed how variant-specific disruption of protein-protein interactions (edgetic perturbations) may contribute to phenotypic variability in PEX26 deficient patients. The discovery of 14 novel protein-protein interactions for PEX26 revealed a hub position of PEX26 inside the peroxisomal interactome. Analysis of edgetic perturbations of PEX26 variants revealed a strong correlation between the number of affected protein-protein interactions and the molecular phenotype of matrix protein import. The role of PEX26 in peroxisomal biogenesis was expanded encompassing matrix protein import, division and proliferation, and membrane assembly. Moreover, the PEX26 interaction network intersects with cellular lipid metabolism at different steps. The results of this study expand the knowledge about the function of PEX26 and refine genotype-phenotype correlations, which may contribute to our understanding of the underlying disease mechanism of PEX26 deficiency.

scholarly journals Pex14p phosphorylation modulates import of citrate synthase 2 into peroxisomes in Saccharomyces cerevisiae

2020 ◽  
Author(s):  
Andreas Schummer ◽  
Renate Maier ◽  
Shiran Gabay-Maskit ◽  
Tobias Hansen ◽  
Wignand W. D. Mühlhäuser ◽  
...  
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Matrix Protein ◽  
Protein Import ◽  
Citrate Synthase ◽  
Glyoxylate Cycle ◽  
Carbon Sources ◽  
The State ◽  
Peroxisomal Biogenesis ◽  
Nutritional Conditions ◽  
Peroxisomal Targeting

AbstractThe peroxisomal biogenesis factor Pex14p is an essential component of the peroxisomal matrix protein import machinery. Together with Pex13p and Pex17p, it is part of the membrane-associated peroxisomal docking complex in yeast, facilitating the binding of cargo-loaded receptor proteins for translocation of cargo proteins into the peroxisome. Furthermore, Pex14p is part of peroxisomal import pores. The central role of Pex14p in peroxisomal matrix protein import processes renders it an obvious target for regulatory mechanisms such as protein phosphorylation. To explore this possibility, we examined the state of Pex14p phosphorylation in Saccharomyces cerevisiae. Phos-tag-SDS-PAGE of Pex14p affinity-purified from solubilized membranes revealed Pex14p as multi-phosphorylated protein. Using mass spectrometry, we identified 16 phosphorylation sites, with phosphorylation hot spots located in the N- and C-terminal regions of Pex14p. Analysis of phosphomimicking and nonphosphorylatable variants of Pex14p revealed a decreased import of GFP carrying a peroxisomal targeting signal type 1, indicating a functional relevance of Pex14p phosphorylation in peroxisomal matrix protein import. We show that this effect can be ascribed to the phosphomimicking mutation at serine 266 of Pex14p (Pex14p-S266D). We further screened the subcellular distribution of 23 native GFP-tagged peroxisomal matrix proteins by high-content fluorescence microscopy. Only Cit2p, the peroxisomal isoform of citrate synthase, was affected in the Pex14p-S266D mutant, showing increased cytosolic localization. Cit2p is part of the glyoxylate cycle, which is required for the production of essential carbohydrates when yeast is grown on non-fermentable carbon sources. Pex14p-S266 phosphosite mutants showed reversed growth phenotypes on oleic acid and ethanol with acetyl-CoA formed in peroxisomes and the cytosol, respectively. Our data point to the control of the peroxisomal import of Cit2p via the state of Pex14p phosphorylation at S266, which may help S. cerevisiae cells to rapidly adjust their carbohydrate metabolism according to the nutritional conditions.

scholarly journals Arabidopsis LON2 Is Necessary for Peroxisomal Function and Sustained Matrix Protein Import

2009 ◽  
Vol 151 (3) ◽  
pp. 1354-1365 ◽  
Author(s):  
Matthew J. Lingard ◽  
Bonnie Bartel
Keyword(s):  
Matrix Protein ◽  
Protein Import ◽  
Peroxisomal Function

Papillon-Lefevre Syndrome: Challenge for Periodontal Management

2019 ◽  
Vol 3 (2) ◽  
pp. 84-86
Author(s):  
Krishna Prasad Lamichhane ◽  
Shaili Pradhan ◽  
Ranjita Shreshta Gorkhali ◽  
Pramod Kumar Koirala
Keyword(s):  
Significant Role ◽  
Autosomal Recessive ◽  
Clinical Manifestations ◽  
Autosomal Recessive Disorder ◽  
Genetic Mutations ◽  
Rare Autosomal Recessive Disorder ◽  
Diagnosis And Management ◽  
Periodontal Destruction ◽  
Palmoplantar Keratosis

Papillon-Lefèvre syndrome (PLS) is a rare autosomal recessive disorder associated with rapidly progressing periodontitis leading to premature loss of deciduous and permanent dentition and diffuse palmoplantar keratosis. Immunologic alterations, genetic mutations, and role of bacteria are some aetiologic factors. Patients present with early periodontal destruction, so periodontists play a significant role in diagnosis and management. This paper reports a case of Papillon- Lefevre syndrome with its clinical manifestations and challenges for periodontal management which was diagnosed in dental department.

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