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A selective ER ‐phagy exerts procollagen quality control via a Calnexin‐ FAM 134B complex
Author(s) -
Forrester Alison,
De Leonibus Chiara,
Grumati Paolo,
Fasana Elisa,
Piemontese Marilina,
Staiano Leopoldo,
Fregno Ilaria,
Raimondi Andrea,
Marazza Alessandro,
Bruno Gemma,
Iavazzo Maria,
Intartaglia Daniela,
Seczynska Marta,
Anken Eelco,
Conte Ivan,
De Matteis Maria Antonietta,
Dikic Ivan,
Molinari Maurizio,
Settembre Carmine
Publication year - 2018
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.201899847
Subject(s) - biology , calnexin , microbiology and biotechnology , endoplasmic reticulum , calreticulin
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 si RNA 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 FAM 134B 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 FAM 134B. In turn, FAM 134B binds the autophagosome membrane‐associated protein LC 3 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 .