Role of AAA-ATPase Cdc48p in Peroxisomal Quality Control

Abstract

The majority of peroxisomal matrix proteins are equipped with a type 1 peroxisomal targeting signal (PTS1), which is recognized in the cytosol by the import receptor Pex5p and targeted to the peroxisomal membrane. After cargo translocation into the peroxisomal lumen, the receptor is monoubiquitinated and recycled to the cytosol in an ATP-dependent manner by the AAA-ATPases Pex1p and Pex6p. Defects in receptor recycling trigger a quality control process by which the receptor is polyubiquitinated, extracted from the membrane 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 conserved among species, it seemed to be missing in bakers yeast. We present the identification and characterization of the RADAR pathway in S. cerevisiae and discover that the AAA-ATPases Msp1p and predominantly Cdc48p together with its co-factors Ufd1p/Npl4p are constituents of this pathway. In the RADAR-pathway, Cdc48p cooperates with the heterodimeric Ufd1p/Npl4p cofactor to pull misfolded, polyubiquitinated receptor out of the peroxisomal membrane for its subsequent degradation.