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

Thomas Mastalski,Rebecca Brinkmeier,Harald W Platta

doi:10.3390/ijms21030867

Thomas Mastalski, Rebecca Brinkmeier + Show 1 more

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https://doi.org/10.3390/ijms21030867

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Abstract

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.

Highlights

Peroxisomes are single membrane-bound organelles that are found in most eukaryotic cells
The autophagic degradation of peroxisomes is indicated by the occurrence of free *green fluorescent protein (GFP) in immunoblots, because GFP is relatively stable within the vacuole, while the Pex11-moiety of the fusion protein is degraded together with the rest of the organelle [16]
In the present study the question was asked whether the matrix protein import defect and functional impairment of a PEX1-deficient strain could be rescued by a specific block of pexophagy via the additional deletion of ATG36 in S. cerevisiae. This question is of relevance because it is important for the understanding of the general role of Pex1 in peroxisome function and homeostasis and the resulting working model

Summary

Introduction

Peroxisomes are single membrane-bound organelles that are found in most eukaryotic cells. Their most conserved function is the breakdown of fatty acids via beta-oxidation as well as the detoxification of the produced H2O2. The AAA (ATPases associated with diverse cellular activities)-type ATPases Pex and Pex and their membrane anchor Pex are essential peroxisomal biogenesis factors [5]. Their importance is indicated by the finding that 65% of all PBD patients suffer from mutations within the human AAA complex genes PEX1 (48.5%), PEX6 (13.1%) or PEX26 (3.4%) [3]. Certain mutations in PEX1, PEX6 or PEX26 were recently shown to be the cause of the Heimler Syndrome [6,7]

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