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MBC in Press, published online ahead of print December 27, 2007
Mol. Biol. Cell 10.1091/mbc.E07-10-1040

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Submitted on October 16, 2007
Revised on December 6, 2007
Accepted on December 19, 2007

Relative Structural and Functional Roles of Multiple Deubiquitylating Proteins Associated with Mammalian 26S Proteasome

Elena Koulich, Xiaohua Li, and George N. DeMartino

Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9040

Monitoring Editor: William Tansey

We determined composition and relative roles of deubiquitylating proteins associated with the 26S proteasome in mammalian cells. Three deubiquitylating activities were associated with the 26S proteasome: two from constituent subunits, Rpn11/S13 and Uch37, and one from a reversibly associated protein, Usp14. RNAi of Rpn11/S13 inhibited cell growth, decreased cellular proteasome activity via disrupted 26S proteasome assembly, and inhibited cellular protein degradation. In contrast, RNAi of Uch37 or Usp14 had no detectable effect on cell growth, proteasome structure or proteolytic capacity, but accelerated cellular protein degradation. RNAi of both Uch37 and Usp14 also had no effect on proteasome structure or proteolytic capacity, but inhibited cellular protein degradation. Thus, proper proteasomal processing of ubiquitylated substrates requires Rpn11 plus either Uch37 or Usp14. Although the latter proteins feature redundant deubiquitylation functions, they also appear to exert noncatatlyic effects on proteasome activity that are similar to but independent of one another. These results reveal unexpected functional relationships among multiple deubiquitylating proteins and suggest a model for mammalian 26S proteasome function whereby their concerted action governs proteasome function by linking deubiquitylation to substrate hydrolysis.

Address correspondence to: George N. DeMartino (george.demartino{at}utsouthwestern.edu)




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