Forrester, Alison Leonibus, Chiara De Grumati, Paolo Fasana, Elisa Piemontese, Marilina Staiano, Leopoldo Fregno, Ilaria Raimondi, Andrea Marazza, Alessandro Bruno, Gemma Iavazzo, Maria Intartaglia, Daniela Seczynska, Marta van Anken, Eelco Conte, Ivan De Matteis, Maria Antonietta Dikic, Ivan Molinari, Maurizio Settembre, Carmine 2018-12-17 Autophagy is a cytosolic quality control process that recognizes substrates through receptor‐mediated mechanisms. Procollagens, the most abundant gene products in Metazoa, are synthesized in the endoplasmic reticulum (ER), and a fraction that fails to attain the native structure is cleared by autophagy. However, how autophagy selectively recognizes misfolded procollagens in the ER lumen is still unknown. We performed siRNA interference, CRISPR‐Cas9 or knockout‐mediated gene deletion of candidate autophagy and ER proteins in collagen producing cells. We found that the ER‐resident lectin chaperone Calnexin (CANX) and the ER‐phagy receptor FAM134B are required for autophagy‐mediated quality control of endogenous procollagens. Mechanistically, CANX acts as co‐receptor that recognizes ER luminal misfolded procollagens and interacts with the ER‐phagy receptor FAM134B. In turn, FAM134B binds the autophagosome membrane‐associated protein LC3 and delivers a portion of ER containing both CANX and procollagen to the lysosome for degradation. Thus, a crosstalk between the ER quality control machinery and the autophagy pathway selectively disposes of proteasome‐resistant misfolded clients from the ER. application/pdf https://susi.usi.ch/global/documents/318855 https://n2t.net/ark:/12658/srd1318855 https://susi.usi.ch/documents/318855/files/Forrester_EMBJ_2019.pdf eng info:eu-repo/semantics/altIdentifier/doi/10.15252/embj.201899847 info:eu-repo/semantics/altIdentifier/ark/12658/srd1318855 info:eu-repo/semantics/openAccess CC BY The EMBO Journal. - 2019, vol. 38, no. 2, p. e99847 autophagy Calnexin collagen endoplasmic reticulum FAM134B info:eu-repo/classification/udc/61 A selective ER‐phagy exerts procollagen quality control via a Calnexin‐FAM134B complex http://purl.org/coar/resource_type/c_6501