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Originally published in Science Express on 15 August 2002
Science 18 October 2002:
Vol. 298. no. 5593, pp. 611 - 615
DOI: 10.1126/science.1075898
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Reports

Role of Rpn11 Metalloprotease in Deubiquitination and Degradation by the 26S Proteasome

Rati Verma,1 L. Aravind,2 Robert Oania,1 W. Hayes McDonald,3 John R. Yates III,3 Eugene V. Koonin,2 Raymond J. Deshaies1*

The 26S proteasome mediates degradation of ubiquitin-conjugated proteins. Although ubiquitin is recycled from proteasome substrates, the molecular basis of deubiquitination at the proteasome and its relation to substrate degradation remain unknown. The Rpn11 subunit of the proteasome lid subcomplex contains a highly conserved Jab1/MPN domain-associated metalloisopeptidase (JAMM) motif--EXnHXHX10D. Mutation of the predicted active-site histidines to alanine (rpn11AXA) was lethal and stabilized ubiquitin pathway substrates in yeast. Rpn11AXA mutant proteasomes assembled normally but failed to either deubiquitinate or degrade ubiquitinated Sic1 in vitro. Our findings reveal an unexpected coupling between substrate deubiquitination and degradation and suggest a unifying rationale for the presence of the lid in eukaryotic proteasomes.

1 Department of Biology and Howard Hughes Medical Institute, California Institute of Technology, Pasadena, CA 91125, USA.
2 National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD 20894, USA.
3 Department of Cell Biology, The Scripps Research Institute, San Diego, CA 92037, USA.
*   To whom correspondence should be addressed. E-mail: deshaies{at}caltech.edu

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J. Biol. Chem. 279, 3916-3924
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Complementary Roles for Rpn11 and Ubp6 in Deubiquitination and Proteolysis by the Proteasome.
A. Guterman and M. H. Glickman (2004)
J. Biol. Chem. 279, 1729-1738
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Specific and Covalent Targeting of Conjugating and Deconjugating Enzymes of Ubiquitin-Like Proteins.
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J. Biol. Chem. 278, 52102-52115
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J. T. Ohlmeyer and T. Schupbach (2003)
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J. Hanna, D. S. Leggett, and D. Finley (2003)
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Development of Protacs to Target Cancer-promoting Proteins for Ubiquitination and Degradation.
K. M. Sakamoto, K. B. Kim, R. Verma, A. Ransick, B. Stein, C. M. Crews, and R. J. Deshaies (2003)
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D. Flierman, Y. Ye, M. Dai, V. Chau, and T. A. Rapoport (2003)
J. Biol. Chem. 278, 34774-34782
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H.-C. S. Yen, C. Espiritu, and E. C. Chang (2003)
J. Biol. Chem. 278, 30669-30676
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T. Gan-Erdene, K. Nagamalleswari, L. Yin, K. Wu, Z.-Q. Pan, and K. D. Wilkinson (2003)
J. Biol. Chem. 278, 28892-28900
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Deubiquitinating Enzymes as Cellular Regulators.
J. H. Kim, K. C. Park, S. S. Chung, O. Bang, and C. H. Chung (2003)
J. Biochem. 134, 9-18
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A Novel Type of Deubiquitinating Enzyme.
P. C. Evans, T. S. Smith, M.-J. Lai, M. G. Williams, D. F. Burke, K. Heyninck**, M. M. Kreike, R. Beyaert, T. L. Blundell, and P. J. Kilshaw (2003)
J. Biol. Chem. 278, 23180-23186
   Abstract »    Full Text »    PDF »
Data-Mining Approaches Reveal Hidden Families of Proteases in the Genome of Malaria Parasite.
Y. Wu, X. Wang, X. Liu, and Y. Wang (2003)
Genome Res. 13, 601-616
   Abstract »    Full Text »    PDF »
The Pleiotropic Role of the 26S Proteasome Subunit RPN10 in Arabidopsis Growth and Development Supports a Substrate-Specific Function in Abscisic Acid Signaling.
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PLANT CELL 15, 965-980
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S. Raasi and C. M. Pickart (2003)
J. Biol. Chem. 278, 8951-8959
   Abstract »    Full Text »    PDF »
Characterization of the Last Subunit of the Arabidopsis COP9 Signalosome: Implications for the Overall Structure and Origin of the Complex.
G. Serino, H. Su, Z. Peng, T. Tsuge, N. Wei, H. Gu, and X. W. Deng (2003)
PLANT CELL 15, 719-731
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Rpn6p, a Proteasome Subunit from Saccharomyces cerevisiae, Is Essential for the Assembly and Activity of the 26 S Proteasome.
P. G. Santamaria, D. Finley, J. P. G. Ballesta, and M. Remacha (2003)
J. Biol. Chem. 278, 6687-6695
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Human Autophagins, a Family of Cysteine Proteinases Potentially Implicated in Cell Degradation by Autophagy.
G. Marino, J. A. Uria, X. S. Puente, V. Quesada, J. Bordallo, and C. Lopez-Otin (2003)
J. Biol. Chem. 278, 3671-3678
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Endoproteolytic Activity of the Proteasome.
C.-W. Liu, M. J. Corboy, G. N. DeMartino, and P. J. Thomas (2003)
Science 299, 408-411
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Functional Characterization of the 11 Non-ATPase Subunit Proteins in the Trypanosome 19 S Proteasomal Regulatory Complex.
Z. Li and C. C. Wang (2002)
J. Biol. Chem. 277, 42686-42693
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Role of Predicted Metalloprotease Motif of Jab1/Csn5 in Cleavage of Nedd8 from Cul1.
G. A. Cope, G. S. B. Suh, L. Aravind, S. E. Schwarz, S. L. Zipursky, E. V. Koonin, and R. J. Deshaies (2002)
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