The UFSP2-C1orf27 complex positions nascent GPCRs to the ufmylation system for ER export control

The ufmylation system is implicated in multiple cellular processes and human diseases; our recent study has identified its function in protein trafficking, but detailed mechanisms remain elusive. Here, we reveal cooperative actions of ufmylation protease UFSP2 and endoplasmic reticulum (ER)-anchored protein C1orf27 on ER-to-Golgi transport of some G protein-coupled receptors (GPCRs). UFSP2 interacts with C1orf27 for ER recruitment, and its activation is dispensable for recruitment but essential for ER export of GPCRs. Structural analysis suggests that UFSP2 and C1orf27 are diverged from a C. elegans ODR8-like protein. Similar to their C. elegans homologs, UFSP2, C1orf27, and cargo GPCRs form a multi-protein complex, and GPCR interaction with C1orf27 is required for their ER export and forward delivery. Collectively, these data demonstrate that the C1orf27-UFSP2 complex interacts with its cargo GPCRs, directs them to ufmylation regulation, and controls their ER export, providing important insights into the trafficking function of the ufmylation system and GPCR maturation processing.