Cargo-interacting regions (CIR) of CCPG1 capture ER luminal cargos for reticulophagy.

The endoplasmic reticulum (ER) is an organelle that regulates several vital processes necessary to maintain the health of eukaryotic cells. Protein quality control systems selectively remove abnormal ER luminal proteins to maintain ER function. In addition to the ubiquitin-proteasome pathway, the lysosome-dependent selective type of autophagy, reticulophagy (or ER-phagy), plays a crucial role in ER proteostasis. Despite the identification of several reticulophagy receptors, the mechanisms by which cytoplasmic reticulophagy machinery recognizes luminal cargo remain largely unknown. We reported that the reticulophagy receptor CCPG1 (cell cycle progression 1) contains several cargo-interacting regions (CIRs) in its ER luminal region that can directly recognize ER luminal cargos. Our findings suggest that CCPG1 is a key player in sequestering ER luminal cargo into the autophagosome using CIRs. Abbreviations: CIR: cargo-interacting region; CCPG1: cell cycle progression 1; FIR: FIP200-interacting region; IAPP: islet amyloid polypeptide; LIR: LC3-interacting region.