title: NEDD8 links cullin-RING ubiquitin ligase function to the p97 pathway.
abstract: 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, for many cofactors ubiquitinated targets have not yet been identified, leaving their biological function unclear. Previous analysis has linked the p97 pathway to cullin-RING ubiquitin ligases (CRLs); here we demonstrate that the human 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 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.
authors.affiliation: Division of Biology, California Institute of Technology, Pasadena, California, USA.
authors.forename: Willem
authors.initials: W
authors.lastname: den Besten
authors.forename: Rati
authors.initials: R
authors.lastname: Verma
authors.forename: Gary
authors.initials: G
authors.lastname: Kleiger
authors.forename: Robert S
authors.initials: RS
authors.lastname: Oania
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Deshaies
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000251:Adenosine Triphosphatases / Q000378:metabolism*; D002352:Carrier Proteins / Q000737:chemistry / Q000378:metabolism*; D002460:Cell Line; D044842:Cullin Proteins / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D000075687:NEDD8 Protein; D009687:Nuclear Proteins / Q000378:metabolism*; D063150:Polycomb Repressive Complex 1; D054730:Protein Interaction Domains and Motifs; D060066:Protein Interaction Maps; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D014452:Ubiquitins / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C105153:CUL2 protein, human; C114234:CUL4A protein, human; D002352:Carrier Proteins; D044842:Cullin Proteins; D004268:DNA-Binding Proteins; D000075687:NEDD8 Protein; C082860:NEDD8 protein, human; D009687:Nuclear Proteins; C531895:UBXN7 protein, human; D025801:Ubiquitin; D014452:Ubiquitins; D063150:Polycomb Repressive Complex 1; C080355:RING1 protein, human; D044767:Ubiquitin-Protein Ligases; D000251:Adenosine Triphosphatases; C404942:p97 ATPase