Nascent Chain Ubiquitination is Uncoupled from Degradation to Enable Protein Maturation

Abstract

A significant proportion of nascent proteins undergo polyubiquitination on ribosomes in mammalian cells, yet the fate of these proteins remains elusive. The ribosome-associated quality control (RQC) is a mechanism that mediates the ubiquitination of nascent chains on stalled ribosomes. Here, we find that nascent proteins ubiquitinated on stalled ribosomes by the RQC E3 ligase LTN1 are insufficient for proteasomal degradation. Our biochemical reconstitution studies reveal that ubiquitinated nascent chains are promptly deubiquitinated in the cytosol upon release from stalled ribosomes, as they are no longer associated with LTN1 E3 ligase for continuous ubiquitination to compete with cytosolic deubiquitinases. These deubiquitinated nascent chains can mature into stable proteins. However, if they misfold and expose a degradation signal, the cytosolic quality control recognizes them for re-ubiquitination and subsequent proteasomal degradation. Thus, our findings suggest that cycles of ubiquitination and deubiquitination spare foldable nascent proteins while ensuring the degradation of terminally misfolded proteins.