A series of ubiquitin binding factors connects CDC48/p97 to substrate multiubiquitylation and proteasomal targeting.
Protein degradation in eukaryotes usually requires multiubiquitylation and subsequent delivery of the tagged substrates to the proteasome. Recent studies suggest the involvement of the AAA ATPase CDC48, its cofactors, and other ubiquitin binding factors in protein degradation, but how these proteins work together is unclear. Here we show that these factors cooperate sequentially through protein-protein interactions and thereby escort ubiquitin-protein conjugates to the proteasome. Central to this pathway is the chaperone CDC48/p97, which coordinates substrate recruitment, E4-catalyzed multiubiquitin chain assembly, and proteasomal targeting. Concomitantly, CDC48 prevents the formation of excessive multiubiquitin chain sizes that are surplus to requirements for degradation. In yeast, this escort pathway guides a transcription factor from its activation in the cytosol to its final degradation and also mediates proteolysis at the endoplasmic reticulum by the ERAD pathway.
Richly
Holger
H
Department of Molecular Cell Biology, Max Planck Institute of Biochemistry, Am Klopferspitz 18, 82152 Martinsried, Germany.
Rape
Michael
M
Braun
Sigurd
S
Rumpf
Sebastian
S
Hoege
Carsten
C
Jentsch
Stefan
S
D000251:Adenosine Triphosphatases; D000818:Animals; D018797:Cell Cycle Proteins / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism; D009097:Multienzyme Complexes / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011485:Protein Binding; D017510:Protein Folding; D044763:Ubiquitin-Conjugating Enzymes / Q000378:metabolism; D014452:Ubiquitins / Q000378:metabolism*; D000074405:Valosin Containing Protein
D018797:Cell Cycle Proteins; D018832:Molecular Chaperones; D009097:Multienzyme Complexes; D014452:Ubiquitins; D044763:Ubiquitin-Conjugating Enzymes; D046988:Proteasome Endopeptidase Complex; D000251:Adenosine Triphosphatases; D000074405:Valosin Containing Protein