biostudies-literatureMa WHoward Hughes Medical InstituteMemorial Sloan-Kettering Cancer Centere26624https://www.ebi.ac.uk/biostudies/studies/S-EPMC5464768biostudies-literatureUnknown6Native cargo proteins exit the endoplasmic reticulum (ER) in COPII-coated vesicles, whereas resident and misfolded proteins are substantially excluded from vesicles by a retention mechanism that remains unresolved. We probed the ER retention process using the proteostasis regulator 4-phenylbutyrate (4-PBA), which we show targets COPII protein to reduce the stringency of retention. 4-PBA competes with p24 proteins to bind COPII. When p24 protein uptake is blocked, COPII vesicles package resident proteins and an ER-trapped mutant LDL receptor. We further show that 4-PBA triggers the secretion of a KDEL-tagged luminal resident, implying that a compromised retention mechanism causes saturation of the KDEL retrieval system. The results indicate that stringent ER retention requires the COPII coaeLifeER retention is imposed by COPII protein sorting and attenuated by 4-phenylbutyrate.PMC5464768P30-CA008748Goldberg EGoldberg JMa WfalseER retention is imposed by COPII protein sorting and attenuated by 4-phenylbutyrate.Native cargo proteins exit the endoplasmic reticulum (ER) in COPII-coated vesicles, whereas resident and misfolded proteins are substantially excluded from vesicles by a retention mechanism that remains unresolved. We probed the ER retention process using the proteostasis regulator 4-phenylbutyrate (4-PBA), which we show targets COPII protein to reduce the stringency of retention. 4-PBA competes with p24 proteins to bind COPII. When p24 protein uptake is blocked, COPII vesicles package resident proteins and an ER-trapped mutant LDL receptor. We further show that 4-PBA triggers the secretion of a KDEL-tagged luminal resident, implying that a compromised retention mechanism causes saturation of the KDEL retrieval system. The results indicate that stringent ER retention requires the COPII coa2017-01-01T00:00:00Z2017 Jun2025-05-31T23:29:52.317Z2025-05-31T23:29:52.317ZS-EPMC54647682859432610.7554/eLife.26624