Cdc48/p97 promotes degradation of aberrant nascent polypeptides bound to the ribosome
Rati Verma,
Robert S Oania,
Natalie J Kolawa,
Raymond J Deshaies
Affiliations
Rati Verma
Division of Biology, California Institute of Technology, Pasadena, United States; Howard Hughes Medical Institute, California Institute of Technology, Pasadena, United States
Robert S Oania
Division of Biology, California Institute of Technology, Pasadena, United States; Howard Hughes Medical Institute, California Institute of Technology, Pasadena, United States
Natalie J Kolawa
Division of Biology, California Institute of Technology, Pasadena, United States
Raymond J Deshaies
Division of Biology, California Institute of Technology, Pasadena, United States; Howard Hughes Medical Institute, California Institute of Technology, Pasadena, United States
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.
