biostudies-literatureTempio TAirc Italian Foundation for Cancer ResearchAssociazione Italiana per la Ricerca sul CancroMinistero dell'Istruzione dell'Università e della RicercaTelethon102244https://www.ebi.ac.uk/biostudies/studies/S-EPMC7973864biostudies-literatureUnknown24(3)The composition of the secretome depends on the combined action of cargo receptors that facilitate protein transport and sequential checkpoints that restrict it to native conformers. Acting after endoplasmic reticulum (ER)-resident chaperones, ERp44 retrieves its clients from downstream compartments. To guarantee efficient quality control, ERp44 should exit the ER as rapidly as its clients, or more. Here, we show that appending ERp44 to different cargo proteins increases their secretion rates. ERp44 binds the cargo receptor ER-Golgi intermediate compartment (ERGIC)-53 in the ER to negotiate preferential loading into COPII vesicles. Silencing ERGIC-53, or competing for its COPII binding with 4-phenylbutyrate, causes secretion of Prdx4, an enzyme that relies on ERp44 for intracellular localiiScienceA virtuous cycle operated by ERp44 and ERGIC-53 guarantees proteostasis in the early secretory compartment.PMC7973864GGP15059Orsi AAnelli TSicari DYoboue EDValetti CTempio TSitia RfalseA virtuous cycle operated by ERp44 and ERGIC-53 guarantees proteostasis in the early secretory compartment.The composition of the secretome depends on the combined action of cargo receptors that facilitate protein transport and sequential checkpoints that restrict it to native conformers. Acting after endoplasmic reticulum (ER)-resident chaperones, ERp44 retrieves its clients from downstream compartments. To guarantee efficient quality control, ERp44 should exit the ER as rapidly as its clients, or more. Here, we show that appending ERp44 to different cargo proteins increases their secretion rates. ERp44 binds the cargo receptor ER-Golgi intermediate compartment (ERGIC)-53 in the ER to negotiate preferential loading into COPII vesicles. Silencing ERGIC-53, or competing for its COPII binding with 4-phenylbutyrate, causes secretion of Prdx4, an enzyme that relies on ERp44 for intracellular locali2021-01-01T00:00:00Z2021 Mar2025-04-04T10:19:15.529Z2025-04-04T10:19:15.529ZS-EPMC79738643376363510.1016/j.isci.2021.102244