A Co-Translational Ubiquitination Pathway For Quality Control of Misfolded Proteins

摘要

Previous studies have indicated that 6–30% of all 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 co-translational 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.