TY - JOUR
T1 - Ubiquitin Chains Are Remodeled at the Proteasome by Opposing Ubiquitin Ligase and Deubiquitinating Activities
AU - Crosas, Bernat
AU - Hanna, John
AU - Kirkpatrick, Donald S.
AU - Zhang, Dan Phoebe
AU - Tone, Yoshiko
AU - Hathaway, Nathaniel A A.
AU - Buecker, Christa
AU - Leggett, David S.
AU - Schmidt, Marion
AU - King, Randall W.
AU - Gygi, Steven P P.
AU - Finley, Daniel
N1 - Funding Information:
This work was supported by NIH grants GM65592 (D.F.), GM67945 (S.P.G.), and GM66492 (R.W.K.); Spanish Government (MEC) grant RyC3582 (B.C.); and a JSPS Postdoctoral Fellowship for Research Abroad (Y.T.). We thank Millennium Pharmaceuticals for the gift of PS341 and R. Baker, M. Hochstrasser, R. Vierstra, D. Kornitzer, R. Li, and C. Mann for antibodies. We also thank S. Elsasser and J. Roelofs for yeast strains.
PY - 2006/12/29
Y1 - 2006/12/29
N2 - The ubiquitin ligase Hul5 was recently identified as a component of the proteasome, a multisubunit protease that degrades ubiquitin-protein conjugates. We report here a proteasome-dependent conjugating activity of Hul5 that endows proteasomes with the capacity to extend ubiquitin chains. hul5 mutants show reduced degradation of multiple proteasome substrates in vivo, suggesting that the polyubiquitin signal that targets substrates to the proteasome can be productively amplified at the proteasome. However, the products of Hul5 conjugation are subject to disassembly by a proteasome-bound deubiquitinating enzyme, Ubp6. A hul5 null mutation suppresses a ubp6 null mutation, suggesting that a balance of chain-extending and chain-trimming activities is required for proper proteasome function. As the association of Hul5 with proteasomes was found to be strongly stabilized by Ubp6, these enzymes may be situated in proximity to one another. We propose that through dynamic remodeling of ubiquitin chains, proteasomes actively regulate substrate commitment to degradation.
AB - The ubiquitin ligase Hul5 was recently identified as a component of the proteasome, a multisubunit protease that degrades ubiquitin-protein conjugates. We report here a proteasome-dependent conjugating activity of Hul5 that endows proteasomes with the capacity to extend ubiquitin chains. hul5 mutants show reduced degradation of multiple proteasome substrates in vivo, suggesting that the polyubiquitin signal that targets substrates to the proteasome can be productively amplified at the proteasome. However, the products of Hul5 conjugation are subject to disassembly by a proteasome-bound deubiquitinating enzyme, Ubp6. A hul5 null mutation suppresses a ubp6 null mutation, suggesting that a balance of chain-extending and chain-trimming activities is required for proper proteasome function. As the association of Hul5 with proteasomes was found to be strongly stabilized by Ubp6, these enzymes may be situated in proximity to one another. We propose that through dynamic remodeling of ubiquitin chains, proteasomes actively regulate substrate commitment to degradation.
UR - http://www.scopus.com/inward/record.url?scp=33845600006&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33845600006&partnerID=8YFLogxK
U2 - 10.1016/j.cell.2006.09.051
DO - 10.1016/j.cell.2006.09.051
M3 - Article
C2 - 17190603
AN - SCOPUS:33845600006
SN - 0092-8674
VL - 127
SP - 1401
EP - 1413
JO - Cell
JF - Cell
IS - 7
ER -