Mechanism of nascent chain removal by the Ribosome-associated Quality Control complex

Errors during translation can cause ribosome stalling, leaving incomplete nascent chains attached to large ribosomal subunits ^1–5 . Cells rely on the Ribosome-associated Quality Control (RQC) complex to recognize, process, and remove these partially synthesized proteins to maintain proteostasis. Despite its central role, the mechanisms by which the RQC complex orchestrates nascent chain processing and extraction have remained unclear. Here, we present a cryo-EM structure of the RQC complex from budding yeast, revealing how its core eukaryotic components function in nascent chain removal. We show that the Cdc48 protein extracting enzyme, along with its Ufd1-Npl4 adaptor, is recruited by the Ltn1 E3 ubiquitin ligase to extract ubiquitylated stalled peptides from the 60S ribosome. Additionally, we find that the Rqc1 component bridges the 60S ribosome with ubiquitin and Ltn1, facilitating the specific formation of K48-linked polyubiquitin chains on stalled peptides. These findings provide a structural and mechanistic framework for understanding how components of the RQC complex work together to remove faulty translation products from the ribosome, advancing our understanding of cellular protein quality control.