biostudies-literatureChen YJNIDDK NIH HHSNIGMS NIH HHSU.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases5991https://www.ebi.ac.uk/biostudies/studies/S-EPMC8514460biostudies-literatureUnknown12(1)The reticulon-3 (RTN3)-driven targeting complex promotes clearance of misfolded prohormones from the endoplasmic reticulum (ER) for lysosomal destruction by ER-phagy. Because RTN3 resides in the cytosolic leaflet of the ER bilayer, the mechanism of selecting misfolded prohormones as ER-phagy cargo on the luminal side of the ER membrane remains unknown. Here we identify the ER transmembrane protein PGRMC1 as an RTN3-binding partner. Via its luminal domain, PGRMC1 captures misfolded prohormones, targeting them for RTN3-dependent ER-phagy. PGRMC1 selects cargos that are smaller than the large size of other reported ER-phagy substrates. Cargos for PGRMC1 include mutant proinsulins that block secretion of wildtype proinsulin through dominant-negative interactions within the ER, causing insulin-Nature communicationsPGRMC1 acts as a size-selective cargo receptor to drive ER-phagic clearance of mutant prohormones.PMC8514460P30 DK020572T32 GM007315F31 DK128868R01 DK048280R01 DK111174Haataja LTsai BKnupp JChen YJArvan PArunagiri AfalsePGRMC1 acts as a size-selective cargo receptor to drive ER-phagic clearance of mutant prohormones.The reticulon-3 (RTN3)-driven targeting complex promotes clearance of misfolded prohormones from the endoplasmic reticulum (ER) for lysosomal destruction by ER-phagy. Because RTN3 resides in the cytosolic leaflet of the ER bilayer, the mechanism of selecting misfolded prohormones as ER-phagy cargo on the luminal side of the ER membrane remains unknown. Here we identify the ER transmembrane protein PGRMC1 as an RTN3-binding partner. Via its luminal domain, PGRMC1 captures misfolded prohormones, targeting them for RTN3-dependent ER-phagy. PGRMC1 selects cargos that are smaller than the large size of other reported ER-phagy substrates. Cargos for PGRMC1 include mutant proinsulins that block secretion of wildtype proinsulin through dominant-negative interactions within the ER, causing insulin-2021-01-01T00:00:00Z2021 Oct2026-05-08T17:12:31.21Z2022-02-11T12:22:26.895ZS-EPMC85144603464580310.1038/s41467-021-26225-8