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

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

doi:10.15252/embj.201899847

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Journal article

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

Forrester, Alison Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy
Leonibus, Chiara De Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy
Grumati, Paolo Institute of Biochemistry II, Goethe University Frankfurt – Medical Faculty, University Hospital, Frankfurt am Main, Germany
Fasana, Elisa Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
Piemontese, Marilina Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy
Staiano, Leopoldo Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy
Fregno, Ilaria Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland - Department of Biology, Swiss Federal Institute of Technology, Zurich, Switzerland
Raimondi, Andrea Experimental Imaging Center, San Raffaele Scientific Institute, Milan, Italy
Marazza, Alessandro Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland - Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland
Bruno, Gemma Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy
Iavazzo, Maria Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy
Intartaglia, Daniela Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy
Seczynska, Marta Institute of Biochemistry II, Goethe University Frankfurt – Medical Faculty, University Hospital, Frankfurt am Main, Germany
van Anken, Eelco Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Ospedale San Raffaele, Milan, Italy
Conte, Ivan Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy
De Matteis, Maria Antonietta Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy - Department of Molecular Medicine and Medical Biotechnologies, University of Naples “Federico II”, Naples, Italy
Dikic, Ivan Institute of Biochemistry II, Goethe University Frankfurt – Medical Faculty, University Hospital, Frankfurt am Main, Germany - Buchmann Institute for Molecular Life Sciences, Goethe University Frankfurt, Frankfurt am Main, Germany
Molinari, Maurizio Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland - School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
Settembre, Carmine Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy - Department of Medical and Translational Science, University of Naples “Federico II”, Naples, Italy

17.12.2018

Published in:

The EMBO Journal. - 2019, vol. 38, no. 2, p. e99847

English 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.

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