Ribosome stalling occurs when translating ribosomes halt, for example due to unusual RNA structures, damaged transcripts, or inefficiently translated codons, often leading to ribosome collisions. Cells normally rely on ribosome surveillance and ribosome-associated quality control (RQC) pathways to detect these stalled complexes, split the ribosomal subunits, and remove incompletely translated polypeptide chains, thereby maintaining translation efficiency. While these mechanisms are well understood in the cytosol, ER-associated ribosomes present a unique challenge: they are anchored to the membrane by their association with the translocon, the machinery that translocates unfolded nascent chains into the ER lumen. Approximately 30% of the proteome is handled by the ER-secretory pathway, making quality control mechanisms of vital importance to the cell. However, the localization of translating ribosomes to the ER membrane limits access to cytosolic rescue factors, raising fundamental questions about how ribosome stalling is resolved at the ER. “The RQC machinery simply can’t resolve stalled ribosomes in the same way,” explains first author Milica Mihailović.
In the cytosol, the canonical ribosome surveillance machinery recognizes collided ribosomes and triggers their dissociation into large and small subunits. This process leaves the large ribosomal subunit bound to an incomplete nascent chain, which is then ubiquitinated and targeted for degradation by the RQC. At the ER, the early steps of ribosome surveillance resemble cytosolic pathways, but clearing stalled nascent chains that remain bound to the translocon requires additional regulatory mechanisms.
In their new study, the researchers identify UFMylation as the missing link. UFMylation is a ubiquitin-like post-translational modification in which the small protein UFM1 is attached to specific targets. The best characterized UFM1 target is the ribosomal protein RPL26, part of the large ribosomal subunit. Acting downstream of initial RQC events, UFMylation of RPL26 loosens ER-bound ribosomes to facilitate access for downstream quality-control factors. Group leader Elif Karagöz explains: “UFMylation modulates ribosome-translocon interaction, allowing access for ribosome-associated quality control factors that otherwise cannot reach the nascent chain.” This conformational change enables the efficient extraction and degradation of stalled nascent polypeptides, and, as Elif says, demonstrates that “ribosome-associated quality control and UFMylation are not parallel pathways – they are tightly linked and work together to clear stalled ribosomes at the ER.”
Together, these findings establish a unified mechanistic model in which canonical ribosome surveillance factors initiate ribosome rescue, while UFMylation reshapes ER-bound ribosomes to enable full clearance of stalled nascent chains by the RQC. Rather than acting independently, the two pathways function as a coordinated system that maintains protein homeostasis during membrane-associated translation and prevents the accumulation of potentially toxic intermediates. By revealing how cells resolve ribosome traffic jams at the ER, the study clarifies a long-standing gap in our understanding of translation quality control. As first author Aleksandra Anisimova summarizes: “Cells constantly generate these stalled ribosomal intermediates in the background, and only when the clearance machinery is disrupted do we realize how essential this process really is.”
DOI: 10.1038/s44318-026-00753-9