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	Mol. Cell Jan (2006); 21(2):261-9
Functional division of substrate processing cofactors of the ubiquitin-selective Cdc48 chaperone-
Rumpf S, Jentsch S
Department of Molecular Cell Biology, Max Planck Institute of Biochemistry, Am Klopferspitz 18, 82152 Martinsried, Germany-
Abstract: Ubiquitin-dependent protein degradation usually involves escort factors that target ubiquitylated substrates to the proteasome- A central element in a major escort pathway is Cdc48, a chaperone-like AAA ATPase that collects ubiquitylated substrates via alternative substrate-recruiting cofactors- Cdc48 also associates with Ufd2, an E4 multiubiquitylation enzyme that adds further ubiquitin moieties to preformed ubiquitin conjugates to promote degradation- Here, we show that E4 can be counteracted in vivo by two distinct mechanisms- First, Ufd3, a WD40 repeat protein, directly competes with Ufd2, because both factors utilize the same docking site on Cdc48- Second, Cdc48 also binds Otu1, a deubiquitylation enzyme, which disassembles multiubiquitin chains- Notably, Cdc48 can bind Otu1 and Ufd3 simultaneously, making a cooperation of both inhibitory mechanisms possible- We propose that the balance between the distinct substrate-processing cofactors may determine whether a substrate is multiubiquitylated and routed to the proteasome for degradation or deubiquitylated and-or released for other purposes-
[PUBMED: 16427015]