Evolving models for peroxisome biogenesis

Abstract

Significant progress has been made towards our understanding of the mechanism of peroxisome formation, in particular concerning sorting of peroxisomal membrane proteins, matrix protein import and organelle multiplication. Here we evaluate the progress made in recent years. We focus mainly on progress made in yeasts. We indicate the gaps in our knowledge and discuss conflicting models.

Figure 1

Model of peroxisomal matrix protein import. (I) Proteins harboring a peroxisomal targeting signal of type 1 (PTS1) are recognized and bound by the import receptor Pex5 in the cytosol. (II) The cargo-loaded receptor is directed to the peroxisomal membrane and binds to the docking complex (Pex13/Pex14/Pex17). (III) The import receptor assembles with Pex14 to form a transient pore and (IV) cargo proteins are transported into the peroxisomal matrix in an unknown manner. Cargo release might involve the function of Pex8 or Pex14. (V) The import receptor is monoubiquitinated at a conserved cysteine by the E2-enzyme complex Pex4/Pex22 in tandem with E3-ligases of the RING-complex (Pex2, Pex10, Pex12). (VI) The ubiquitinated receptor is released from the peroxisomal membrane in an ATP-dependent manner by the AAA-peroxins Pex1 and Pex6, which are anchored to the peroxisomal membrane via Pex15. As the last step of the cycle, the ubiquitin moiety is removed and the receptor enters a new round of import. The designation is based on the yeast nomenclature.

Figure 2

Schematic representation of models for peroxisome multiplication. The vesicle fusion model proposes that all PMPs enter the ER, where they segregate and exit the ER in distinct vesicles: vesicles containing the docking complex proteins Pex13,14 (blue) fuse with vesicles containing the RING-finger complex proteins Pex2,10,12 (green) forming a preperoxisomal membrane structure (black). As this membrane structure now contains a complete importomer, matrix protein import commences. Subsequent fission results in peroxisomes of final size and membrane protein composition (red). The growth and division model proposes that peroxisomes (red) are derived from existing peroxisomes by fission. A small subset of PMPs (Class 2) insert into the ER and exit it in a transport vesicle (blue) that fuses with existing peroxisomes, where it provides the docking site for Pex19-mediated import of Class 1 PMPs (Class 1). Since Pex3 can only be detected in peroxisomes in wild type cells it cannot be excluded that it inserts directly into peroxisomes. Reintroduction of Peroxisomes. In the absence of pre-existing peroxisomes, the ER-derived Pex3-containing vesicle matures slowly into a peroxisome, with Pex3 again providing a docking site for Pex19/Class I PMPs complexes; this vesicle is thus slowly converted into a membrane structure containing all PMPs (black), finally becoming import-competent for matrix proteins (red). These newly formed peroxisomes will further multiply by growth and division. Whether Pex13 and Pex14 traffic via the ER or insert directly into a membrane structure distinct from the ER is not established.