Chaperone-mediated pathway of proteasome regulatory particle assembly

Jeroen Roelofs, Soyeon Park, Wilhelm Haas, Geng Tian, Fiona E. McAllister, Ying Huo, Byung Hoon Lee, Fan Zhang, Yigong Shi, Steven P. Gygi, Daniel Finley

Research output: Contribution to journalArticlepeer-review

154 Scopus citations

Abstract

The proteasome is a protease that controls diverse processes in eukaryotic cells. Its regulatory particle (RP) initiates the degradation of ubiquitin-protein conjugates by unfolding the substrate and translocating it into the proteasome core particle (CP) to be degraded. The RP has 19 subunits, and their pathway of assembly is not understood. Here we show that in the yeast Saccharomyces cerevisiae three proteins are found associated with RP but not with the RP-CP holoenzyme: Nas6, Rpn14 and Hsm3. Mutations in the corresponding genes confer proteasome loss-of-function phenotypes, despite their virtual absence from the holoenzyme. These effects result from deficient RP assembly. Thus, Nas6, Rpn14 and Hsm3 are RP chaperones. The RP contains six ATPases-the Rpt proteins-and each RP chaperone binds to the carboxy-terminal domain of a specific Rpt. We show in an accompanying study that RP assembly is templated through the Rpt C termini, apparently by their insertion into binding pockets in the CP. Thus, RP chaperones may regulate proteasome assembly by directly restricting the accessibility of Rpt C termini to the CP. In addition, competition between the RP chaperones and the CP for Rpt engagement may explain the release of RP chaperones as proteasomes mature.

Original languageEnglish
Pages (from-to)861-865
Number of pages5
JournalNature
Volume459
Issue number7248
DOIs
StatePublished - 11 Jun 2009

Bibliographical note

Funding Information:
Acknowledgements We thank C. Mann for Rpt1 (also known as Cim5) and Rpt6 (Cim3) antibodies, K. Kubota for preparing HeLa lysates and especially L. Huang for the human Rpn112HTBH-expressing cell line. We also thank J. Hanna, M. Schmidt and members of the Finley laboratory, in particular S. Elsasser, for critically reading the manuscript. This work was supported by the NIH (GM043601 to D.F. and GM67945 to S.P.G.), a NIH NRSA postdoctoral fellowship (5F32GM75737-2 to S.P.) and an EMBO long-term fellowship (to J.R.).

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