title: A cotranslational ubiquitination pathway for quality control of misfolded proteins.
abstract: Previous studies have indicated that 6%-30% of newly synthesized proteins are rapidly degraded by the ubiquitin-proteasome system; however, the relationship of ubiquitination to translation for these proteins has been unclear. We report that cotranslational ubiquitination (CTU) is a robust process, with 12%-15% of nascent polypeptides being ubiquitinated in human cells. CTU products contained primarily K48-linked polyubiquitin chains, consistent with a proteasomal targeting function. While nascent chains have been shown previously to be ubiquitinated within stalled complexes (CTU(S)), the majority of nascent chain ubiquitination occurred within active translation complexes (CTU(A)). CTU(A) was increased in response to agents that induce protein misfolding, while CTU(S) was increased in response to agents that lead to translational errors or stalling. These results indicate that ubiquitination of nascent polypeptides occurs in two contexts and define CTU(A) as a component of a quality control system that marks proteins for destruction while they are being synthesized.
authors.affiliation: Institute for Cellular and Molecular Biology, Section of Molecular Genetics and Molecular Biology, University of Texas at Austin, Austin, TX 78712, USA.
authors.forename: Feng
authors.initials: F
authors.lastname: Wang
authors.forename: Larissa A
authors.initials: LA
authors.lastname: Durfee
authors.forename: Jon M
authors.initials: JM
authors.lastname: Huibregtse
mesh_terms: D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D003600:Cytosol / Q000378:metabolism; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D010455:Peptides / Q000235:genetics / Q000378:metabolism; D025821:Polyubiquitin / Q000235:genetics / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism; D017510:Protein Folding; D011499:Protein Processing, Post-Translational; D011506:Proteins / Q000737:chemistry / Q000378:metabolism*; D011786:Quality Control; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism; D054875:Ubiquitination
chemical_list: D010455:Peptides; D011506:Proteins; D025821:Polyubiquitin; D046988:Proteasome Endopeptidase Complex