A selective ER‐phagy exerts procollagen quality control via a Calnexin‐FAM134B complex

Autophagy is a cytosolic quality control process that recognizessubstrates through receptor-mediated mechanisms. Procollagens,the most abundant gene products in Metazoa, are synthesized inthe endoplasmic reticulum (ER), and a fraction that fails to attainthe native structure is cleared by autophagy. However, how auto-phagy selectively recognizes misfolded procollagens in the ERlumen is still unknown. We performed siRNA interference, CRISPR-Cas9or knockout-mediated gene deletion of candidate autophagyand ER proteins in collagen producing cells. We found that the ER-resident lectin chaperone Calnexin (CANX) and the ER-phagyreceptor FAM134B are required for autophagy-mediated qualitycontrol of endogenous procollagens. Mechanistically, CANX acts asco-receptor that recognizes ER luminal misfolded procollagens andinteracts with the ER-phagy receptor FAM134B. In turn, FAM134Bbinds the autophagosome membrane-associated protein LC3anddelivers a portion of ER containing both CANX and procollagen tothe lysosome for degradation. Thus, a crosstalk between the ERquality control machinery and the autophagy pathway selectivelydisposes of proteasome-resistant misfolded clients from the ER.