NEDD8 links Cullin–Ring ubiquitin Ligase function to the p97 pathway

The AAA ATPase p97 and its UBA-UBX cofactors are thought to extract ubiquitinated proteins from membranes or protein complexes as a prelude to their degradation. However, ubiquitinated targets have not yet been identified for many cofactors, leaving their biological function unclear. Previous analysis has linked the p97 pathway to Cullin-RING ubiquitin Ligases (CRLs); here we demonstrate that the p97 cofactor UBXD7 mediates the p97-CRL interaction through its conserved ubiquitin-interacting motif (UIM). UBXD7, and its yeast ortholog Ubx5, associate only with the active, NEDD8- or Rub1-modified form of cullins. Disruption of the Ubx5 UIM motif results in a loss of CRL binding and consequently impedes degradation of a Cul3 substrate. These results uncover an unexpected and conserved role for NEDD8 in linking CRL ubiquitin ligase function to the p97 pathway.