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Peroxisomes are near-ubiquitous eukaryotic organelles with a prominent function in the breakdown of fatty acids and hydrogen peroxide. Peroxisomal β-oxidation is characterized by a close metabolic connection between peroxisomes and mitochondria. Peroxisomal acetyl-CoA is transported to mitochondria where it enters the tricarboxylic acid cycle.
In the yeast Saccharomyces cerevisiae almost all peroxisomal matrix proteins contain a peroxisomal targeting signal type 1 (PTS1) at their extreme C-terminus. This signal is recognized by the cytosolic receptor Pex5, which can translocate matrix proteins across the peroxisomal membrane in a fully folded state and even as oligomers.
In this work the protein phosphatase Ptc5 was shown to display a dual localization to mitochondria and peroxisomes. Peroxisomal localization of the phosphatase was dependent on a functional PTS1, the import receptor Pex5 and an intact peroxisomal import machinery. Surprisingly, processing by the mitochondrial inner membrane peptidase (IMP) complex was another prerequisite for the peroxisomal localization of Ptc5. More detailed analysis revealed that sorting of Ptc5 involves simultaneous interaction with the import machineries of peroxisomes and mitochondria resulting in a molecular tug-of-war like mechanism. This can also establish contacts between mitochondria and peroxisomes. Fusion of a PTS1 to the C-terminus of the ER-resident membrane protein Sec63 created a synthetic tether generating contacts between the ER and peroxisomes. Analysis of the biological relevance of tug-of-war like protein sorting revealed that indirect import of Ptc5 in peroxisomes prevents deleterious phosphatase activity in the cytosol. Additional data indicate that intraperoxisomal Ptc5 dephosphorylates glycerol-3-phoshpate dehydrogenase Gpd1 to regulate its activity.
Molecular tug-of-war between import machineries of two compartments represents a novel protein sorting mechanism. Furthermore, this mechanism enables organelle contacts and might facilitate interorganellar communication.