Regulation des Abbaus von Cdc48-Substraten durch die antagonistischen Aktivitäten von Ufd2 und Ufd3

The ubiquitin-proteasome system (UPS) is the major system for
nucleo-/cytoplasmic proteolysis in eukaryotes. Here, proteolytic
substrates are recognized by the proteasome, a large protease,
after their covalent modification with chains of the small protein
ubiquitin. Chaperones are important components of the UPS. In
yeast, the AAA ATPase Cdc48 mediates the degradation of artificial
Ubiquitin Fusion Degradation (UFD) substrates and of Spt23 p90, a
transcription factor that regulates the OLE1 gene. In these
processes, Cdc48 is assisted by multiple accessory factors, such as
the ubiquitin E4 enzyme Ufd2 or Ufd3, a protein of unclear
function. ufd3 mutants display certain similarities to mutants in
deubiquitylating enzymes. Here, I show that Ufd2/E4 and Ufd3 bind
to Cdc48 via the same interaction site and compete with each other
for Cdc48 binding. Ufd2 binding results in substrate
multiubiquitylation and degradation via the proteasomal receptors
Rad23 and Dsk2, which interact with Ufd2. Ufd3 binding to Cdc48
blocks this pathway and results in the stabilization of Cdc48
substrates. In this function, Ufd3 is assisted by the newly
identified deubiquitylating enzyme Otu1 which also interacts with
Cdc48. In conclusion, the stability of Cdc48 substrates is
determined by an equilibrium between the antagonistic activities of
Ufd2/E4, Ufd3 and Otu1.