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Published January 22, 2013 | Published
Journal Article Open

Cdc48/p97 promotes degradation of aberrant nascent polypeptides bound to the ribosome


Ubiquitin-dependent proteolysis can initiate at ribosomes for myriad reasons including misfolding of a nascent chain or stalling of the ribosome during translation of mRNA. Clearance of a stalled complex is required to recycle the ribosome for future use. Here we show that the ubiquitin (Ub) pathway segregase Cdc48/p97 and its adaptors Ufd1-Npl4 participate in ribosome-associated degradation (RAD) by mediating the clearance of ubiquitinated, tRNA-linked nascent peptides from ribosomes. Through characterization of both endogenously-generated and heterologous model substrates for the RAD pathway, we conclude that budding yeast Cdc48 functions downstream of the Ub ligases Ltn1 and Ubr1 to release nascent proteins from the ribosome so that they can be degraded by the proteasome. Defective RAD could contribute to the pathophysiology of human diseases caused by mutations in p97.

Additional Information

© 2013 Verma et al. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited. Received: 06 October 2012; Accepted: 21 December 2012; Published: 22 January 2013. We thank Drs. Tsui-Fen Chou, Andre Gerber, Dale Haines, Ambro van Hoof, Claudio Joazeiro, Ernst Jarosch, Roy Parker, Matthew Sachs, Thomas Sommer, Peter Walter and Jonathan Warner for reagents. David Akopian's help in using the sucrose gradient fractionator in the Shu-Ou-Shan laboratory is gratefully acknowledged. We thank current and ex-members of the Deshaies Lab for fruitful discussions, particularly Drs. Gary Kleiger and Willem den Besten. Finally, we thank Jonathan Weissman and Ramanujan Hegde for sharing data prior to publication. Author contributions: RV, Conception and design, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article; RSO, Acquisition of data; NJK, Acquisition of data; RJD, Conception and design, Analysis and interpretation of data, Drafting or revising the article.

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