Export-deficient monoubiquitinated PEX5 triggers peroxisome removal in SV40 large T antigen-transformed mouse embryonic fibroblasts

  title={Export-deficient monoubiquitinated PEX5 triggers peroxisome removal in SV40 large T antigen-transformed mouse embryonic fibroblasts},
  author={Marcus Nordgren and T{\^a}nia Francisco and Celien Lismont and Lore Hennebel and Chantal Brees and Bo Wang and Paul P. Van Veldhoven and Jorge E Azevedo and Marc Fransen},
  pages={1326 - 1340}
Peroxisomes are ubiquitous cell organelles essential for human health. To maintain a healthy cellular environment, dysfunctional and superfluous peroxisomes need to be selectively removed. Although emerging evidence suggests that peroxisomes are mainly degraded by pexophagy, little is known about the triggers and molecular mechanisms underlying this process in mammalian cells. In this study, we show that PEX5 proteins fused to a bulky C-terminal tag trigger peroxisome degradation in SV40 large… 

Deubiquitinating enzyme USP30 maintains basal peroxisome abundance by regulating pexophagy

It is reported here that USP30, best known as a mitophagy regulator, is also necessary for regulating pexophagy, the selective autophagic degradation of peroxisomes.

Disparate peroxisome‐related defects in Arabidopsis pex6 and pex26 mutants link peroxisomal retrotranslocation and oil body utilization

Peroxisomes clustered around persisting oil bodies in pex6 and pex26 seedlings, suggesting a role for peroxisomal retrotranslocation machinery in oil body utilization.

Peroxisomal monoubiquitinated PEX5 interacts with the AAA ATPases PEX1 and PEX6 and is unfolded during its dislocation into the cytosol

Evidence is provided suggesting that DTM-embedded Ub-PEX5 interacts directly with both PEX1 and PEX6 through its ubiquitin moiety and that the PEX5 polypeptide chain is globally unfolded during the ATP-dependent extraction event.

The peroxisomal exportomer directly inhibits phosphoactivation of the pexophagy receptor Atg36 to suppress pexophagy in yeast

A mechanism by which a compartment-specific AAA+ complex mediating organelle biogenesis and protein quality control staves off induction of selective autophagy is uncovered.

Peroxisomal ATPase ATAD1 acts in quality control of the protein import machinery

The influence of ATAD1 is shown on the stability of accumulated PEX5 and a role in a peroxisomal quality control mechanism enabling clearance of ubiquitinated receptor from the membrane is hypothesized.

The peroxisomal AAA ATPase complex prevents pexophagy and development of peroxisome biogenesis disorders

It is shown here that loss of the AAA-complex does not prevent matrix protein import, but instead causes an upregulation of peroxisome degradation by macroautophagy, or pexophagy.

Peroxisomes as Modulators of Cellular Protein Thiol Oxidation: A New Model System.

The development of a human cell line that can be used to selectively generate H2O2 inside peroxisomes in a time- and dose-controlled manner and the extent of protein oxidation depends on the subcellular location of the target protein and is inversely correlated to catalase activity and cellular glutathione content are reported.

Peroxisome biogenesis and human peroxisome-deficiency disorders

  • Y. Fujiki
  • Biology
    Proceedings of the Japan Academy. Series B, Physical and biological sciences
  • 2016
Successful cloning of PEX genes encoding peroxins required for peroxisome assembly invaluably contributed to the accomplishment of cloning of pathogenic genes responsible for PBDs.

Pexophagy is responsible for 65% of cases of peroxisome biogenesis disorders

Recognizing PEX1, PEX6 and PEX26 as pexophagy suppressors will allow treating patients with a new range of tools designed to target mammalian pexphagy, and raised hope for up to 65% of all PBD patients with various deficiencies in the AAA-complex.



PEX5, the Shuttling Import Receptor for Peroxisomal Matrix Proteins, Is a Redox‐Sensitive Protein

Findings reveal that the activity of PEX5, and hence PTS1 import, is controlled by the redox state of the cytosol, and that substitution of Cys11 by a lysine can counteract this effect.

The membrane peroxin PEX3 induces peroxisome-ubiquitination-linked pexophagy

Results indicate that ubiquitin- and NBR1-mediated pexophagy is induced by increased expression of PEX3 in mammalian cells, and an endogenous, unidentified peroxisomal protein is ubiquitinated on the peroxISomal membrane.

Characterization of the Peroxisomal Cycling Receptor, Pex5p, Using a Cell-free in Vitro Import System*

The data suggest that translocation of PTS1-containing proteins across the peroxisomal membrane occurs concomitantly with formation of the Pex5p-Pex14p membrane complex and that this is probably the site from which PEx5p leaves the per oxisomal compartment.

Deficiency of the exportomer components Pex1, Pex6, and Pex15 causes enhanced pexophagy in Saccharomyces cerevisiae

It is shown by genetic analysis that preventing this accumulation of ubiquitinated receptors at the peroxisomal membrane does not abolish pexophagy in Saccharomyces cerevisiae, and Atg36 is modified in pex1Δ cells even when Atg11 binding is prevented.

A PEX7-Centered Perspective on the Peroxisomal Targeting Signal Type 2-Mediated Protein Import Pathway

It is found that export of peroxisomal PEX7 back into the cytosol requires export of PEX5 but, strikingly, the two export events are not strictly coupled, indicating that the two proteins leave theperoxisome separately.

Peroxisome Dynamics in Cultured Mammalian Cells

It is shown that peroxisomes display an age‐related heterogeneity with respect to their capacity to incorporate newly synthesized proteins, and it is demonstrated that these organelles do not exchange their protein content.

Cysteine Ubiquitination of PTS1 Receptor Pex5p Regulates Pex5p Recycling

Pex5p is the cytosolic receptor for peroxisome matrix proteins with peroxisome‐targeting signal (PTS) type 1 and shuttles between the cytosol and peroxisomes. Here, we show that Pex5p is

A Conserved Cysteine Residue of Pichia pastoris Pex20p Is Essential for Its Recycling from the Peroxisome to the Cytosol*

A role for Cys-8 in Pex20p recycling is suggested and that constitutive degradation of peroxisomal receptors can be a partially functional alternative to receptor recycling.

Insertion of Pex5p into the Peroxisomal Membrane Is Cargo Protein-dependent*

It is shown that insertion of Pex5p into the peroxisomal membrane requires the presence of cargo proteins, and the results suggest that the cytosol/peroxisome cycle in which Pex 5p is involved is directly or indirectly regulated by Pex7p itself and not by the perxisomal docking/translocation machinery.

Properties of the Ubiquitin-Pex5p Thiol Ester Conjugate*

The data suggest that soluble Ub-Pex5p is deubiquitinated by a combination of context-dependent enzymatic and nonenzymatic mechanisms, and substitution of the conserved cysteine residue of PEx5p by a lysine results in a quite functional protein both in vitro and in vivo.