Recent advances in peroxisomal matrix protein import

Abstract

Peroxisomes are essential organelles responsible for many metabolic reactions, such as the oxidation of very long chain and branched fatty acids, D-amino acids and polyamines, as well as the production and turnover of hydrogen peroxide. They comprise a class of organelles called microbodies, including glycosomes, glyoxysomes and Woronin bodies. Dysfunction of human peroxisomes causes severe and often fatal peroxisome biogenesis disorders (PBDs). Peroxisomal matrix protein import is mediated by receptors that shuttle between the cytosol and peroxisomal matrix using ubiquitination/deubiquitination reactions and ATP hydrolysis for receptor recycling. We focus on the machinery involved in the peroxisomal matrix protein import cycle, highlighting recent advances in peroxisomal matrix protein import, cargo release and receptor recycling/degradation.

Figure 1

PTS receptor dynamics during peroxisomal matrix protein import. The shuttling of PTS receptors and co-receptors between the cytosol and the peroxisomal matrix can be divided into distinct steps: cargo-receptor recognition, receptor-cargo complex translocation across peroxisomal membrane, dissociation of receptor-cargo complex, receptor export to the cytosolic side of peroxisomal membrane, receptor ubiquitination and release to the cytosol, and deubiquitination for next round import. D: docking subcomplex; R: RING subcomplex; RR: receptor recycling machinery. The circle associated with the cargo denotes the PTS.

Figure 2

Ubiquitination/deubiquitination of PTS1 receptor (Pex5) and PTS2 co-receptor (Pex18) during receptor recycling and degradation in S. cerevisiae. Three ubiquitin ligases Pex2, Pex10 and Pex12 form the RING subcomplex and together with ubiquitin-conjugating enzymes, Pex4/Ubc4, are responsible for receptor ubiquitination. Pex10 brings the E2 ubiquitin-conjugating enzyme, Pex4, which is anchored to the peroxisomal membrane via Pex22, into association with the RING subcomplex. Pex5 is mono-ubiquitinated on the conserved N-terminal cysteine C6 by Pex4 and Pex12. The AAA peroxins, Pex1 and Pex6, which are anchored at the peroxisomal membrane by binding to Pex15, recognize mono-ubiquitinated Pex5 directly or indirectly and dislocate it from the membrane back to the cytosol in an ATP-dependent manner. The mono-ubiquitinated Pex5 is deubiquitinated by Ubp15, which binds to Pex6, and is recycled for the next round of import. When the receptor recycling is impaired, Pex5 is poly-ubiquitinated on the conserved N-terminal lysines, K18 and K24, by Ubc4 (E2) and Pex2 (E3 ligase) and then degraded by the proteasome via the RADAR pathway. Pex18 is mono-ubiquitinated on the conserved N-terminal cysteine C6 (for receptor recycling), or is poly-ubiquitinated on the conserved N-terminal lysines, K13 and K20, for degradation by the RADAR pathway.