UFMylation orchestrates spatiotemporal coordination of RQC at the ER.

Abstract

Degradation of arrest peptides from endoplasmic reticulum (ER) translocon-bound 60<i>S</i> ribosomal subunits via the ribosome-associated quality control (ER-RQC) pathway requires covalent modification of RPL26/uL24 on 60<i>S</i> ribosomal subunits with UFM1. However, the underlying mechanism that coordinates the UFMylation and RQC pathways remains elusive. Structural analysis of ER-RQC intermediates revealed concomitant binding and direct interaction of the UFMylation and RQC machineries on the 60<i>S</i>. In the presence of an arrested peptidyl-transfer RNA, the RQC factor NEMF and the UFM1 E3 ligase (E3^UFM1) form a direct interaction via the UFL1 subunit of E3^UFM1, and UFL1 adopts a conformation distinct from that previously observed for posttermination 60<i>S</i>. While this concomitant binding occurs on translocon-bound 60<i>S</i>, LTN1 recruitment and arrest peptide degradation require UFMylation-dependent 60<i>S</i> dissociation from the translocon. These data reveal a mechanism by which the UFMylation cycle orchestrates ER-RQC.