Role of AAA-ATPase Cdc48p in peroxisomal quality control

Most peroxisomal matrix proteins contain a type 1 peroxisomal targeting signal (PTS1), which is recognized by the cytosolic receptor Pex5p for delivery into peroxisomes. Following cargo translocation, the receptor is monoubiquitinated and recycled to the cytosol by the AAA-ATPases Pex1p and Pex6p. Defects in recycling trigger a quality control process by which the receptor is polyubiquitinated, extracted, and targeted to the proteasome for degradation by the RADAR (receptor accumulation and degradation in the absence of recycling) pathway. Although the RADAR pathway is evolutionarily conserved, it is unknown whether it is active in Saccharomyces cerevisiae. Here, we identify and characterize the RADAR pathway in S. cerevisiae and discover that the AAA-ATPases Msp1p and predominantly Cdc48p, together with its cofactors Ufd1p/Npl4p, are constituents of this pathway. We conclude that peroxisomes contain an endoplasmic reticulum-associated degradation-like protein quality control system (RADAR) in which Cdc48p and Ufd1p/Npl4p extract misfolded, polyubiquitinated receptors from the peroxisomal membrane for proteasomal degradation.