A Cotranslational Ubiquitination Pathway for Quality Control of Misfolded Proteins

SummaryPrevious 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 (CTUS), the majority of nascent chain ubiquitination occurred within active translation complexes (CTUA). CTUA was increased in response to agents that induce protein misfolding, while CTUS 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 CTUA as a component of a quality control system that marks proteins for destruction while they are being synthesized.

Graphical AbstractFigure optionsDownload full-size imageDownload high-quality image (159 K)Download as PowerPoint slideHighlights► Cotranslational ubiquitination (CTU) of nascent polypeptides is a robust process ► CTU occurs on both active (CTUA) and stalled (CTUS) translation complexes ► Nascent polypeptides are polyubiquitinated, primarily with K48 chains ► CTUA is enhanced in response to protein misfolding