A Systematic Cell-Based Analysis of Localization of PredictedDrosophilaPeroxisomal Proteins

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Peroxisome biogenesis in Drosophila peroxisomes. Drosophila peroxisomes consist of a membrane (black) surrounding a protein matrix (blue). In peroxisome targeting sequence 1 (PTS1) directed matrix protein import (red), Pex5 (5) binds PTS1 and traffics its cargo to the peroxisomal membrane, where it interacts with the pore-forming complex comprised of Pex13 (13) and Pex14 (14) and the RING-finger complex made up of Pex2 (2), Pex10 (10) and Pex12 (12). Pex5 and its cargo cross the peroxisomal membrane, and Pex5 dissociates from its cargo in the peroxisomal matrix and is recycled to the cytosol by a complex composed of the AAA-ATPases Pex1 and Pex6, an unknown membrane anchor (X), and the RING-finger complex (green). Other matrix proteins lacking a canonical PTS1 are trafficked to the peroxisome by an unknown factor (black, X). There is no evidence of a PTS2 import pathway in Drosophila. A protein (7?) homologous to the PTS2 receptor Pex7 of other organisms localizes to both the cytosol and the peroxisome; its function is undetermined. In peroxisomal membrane protein targeting (mPTS, purple), Pex19 binds to a mPTS and traffics cargo to the peroxisome, where it interacts with Pex3 (3) in complex with Pex16 (16). The mPTS-containing cargo is inserted into the peroxisomal membrane, and Pex19 (19) is released back to the cytosol. Peroxisomal membrane protein targeting can also occur at the level of the endoplasmic reticulum (not shown). Mature peroxisomes can proliferate by fission (orange), in which Pex11A/B (11A/B) and Pex11C (11C) participate in the elongation of the peroxisome and its scission into two daughter organelles.

Peroxisomes are membrane-bound organelles found in almost all eukaryotic cells. They perform specialized biochemical functions that vary with organism, tissue or cell type. Mutations in human genes required for the assembly of peroxisomes result in a spectrum of diseases called the peroxisome biogenesis disorders. A previous sequence-based comparison of the predicted proteome of Drosophila melanogaster (the fruit fly) to human proteins identified 82 potential homologues of proteins involved in peroxisomal biogenesis, homeostasis or metabolism. However, the subcellular localization of these proteins relative to the peroxisome was not determined. Accordingly, we tested systematically the localization and selected functions of epitope-tagged proteins in Drosophila Schneider 2 cells to determine the subcellular localization of 82 potential Drosophila peroxisomal protein homologues. Excluding the Pex proteins, 34 proteins localized primarily to the peroxisome, 8 showed dual localization to the peroxisome and other structures, and 26 localized exclusively to organelles other than the peroxisome. Drosophila is a well-developed laboratory animal often used for discovery of gene pathways, including those linked to human disease. Our work establishes a basic understanding of peroxisome protein localization in Drosophila. This will facilitate use of Drosophila as a genetically tractable, multicellular model system for studying key aspects of human peroxisome disease.

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