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

• Alison Forrester ^[1] ; Chiara De Leonibus ^[1] ; Paolo Grumati ^[2] ; Elisa Fasana ^[3] ; Marilina Piemontese ^[1] ; Leopoldo Staiano ^[1] ; Ilaria Fregno ^[4] ; Andrea Raimondi ^[5] ; Alessandro Marazza ^[6] ; Gemma Bruno ^[1] ; Maria Iavazzo ^[1] ; Daniela Intartaglia ^[1] ; Marta Seczynska ^[2] ; Eelco van Anken ^[7] ; Ivan Conte ^[1] ; Maria Antonietta De Matteis ^[1] ; Ivan Dikic ^[8] ; Maurizio Molinari ^[9] ; Carmine Settembre ^[1]
  1. [1] Telethon Institute Of Genetics And Medicine

     Telethon Institute Of Genetics And Medicine

     Nápoles, Italia

     
  2. [2] 2 Institute of Biochemistry II Goethe University Frankfurt – Medical Faculty University Hospital Frankfurt am Main Germany
  3. [3] 3 Faculty of Biomedical Sciences Institute for Research in Biomedicine Università della Svizzera italiana (USI) Bellinzona Switzerland
  4. [4] 3 Faculty of Biomedical Sciences Institute for Research in Biomedicine Università della Svizzera italiana (USI) Bellinzona Switzerland; 4 Department of Biology Swiss Federal Institute of Technology Zurich Switzerland
  5. [5] 5 Experimental Imaging Center San Raffaele Scientific Institute Milan Italy
  6. [6] 3 Faculty of Biomedical Sciences Institute for Research in Biomedicine Università della Svizzera italiana (USI) Bellinzona Switzerland; 6 Graduate School for Cellular and Biomedical Sciences University of Bern Bern Switzerland
  7. [7] 7 Division of Genetics and Cell Biology San Raffaele Scientific Institute Ospedale San Raffaele Milan Italy
  8. [8] 2 Institute of Biochemistry II Goethe University Frankfurt – Medical Faculty University Hospital Frankfurt am Main Germany; 9 Buchmann Institute for Molecular Life Sciences Goethe University Frankfurt Frankfurt am Main Germany
  9. [9] 3 Faculty of Biomedical Sciences Institute for Research in Biomedicine Università della Svizzera italiana (USI) Bellinzona Switzerland; 10 School of Life Sciences École Polytechnique Fédérale de Lausanne Lausanne Switzerland

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• Localización: EMBO journal: European Molecular Biology Organization, ISSN 0261-4189, Vol. 38, Nº. 2, 2019, pág. 4
• Idioma: inglés
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  • 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.