@article{58c7ea0452424f2e86f1e737d3492d06,
title = "A selective ER-phagy exerts procollagen quality control via a Calnexin-FAM134B complex",
abstract = "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.",
keywords = "autophagy, Calnexin, collagen, endoplasmic reticulum, FAM134B",
author = "Alison Forrester and {De Leonibus}, Chiara and Paolo Grumati and Elisa Fasana and Marilina Piemontese and Leopoldo Staiano and Ilaria Fregno and Andrea Raimondi and Alessandro Marazza and Gemma Bruno and Maria Iavazzo and Daniela Intartaglia and Marta Seczynska and {van Anken}, Eelco and Ivan Conte and {De Matteis}, {Maria Antonietta} and Ivan Dikic and Maurizio Molinari and Carmine Settembre",
note = "Funding Information: We thank G. Diez Roux, A. Ballabio, C Di Malta, G. Napolitano, and L. Soria (TIGEM) for suggestions and critical reading of the manuscript; we thank C. Lanzara and L. Cinque for support and C{\'e}sar Valades Cruz for support in live cell image processing and movie creation. The authors acknowledge Euro-BioImaging (www.eurobioimaging.eu) for providing access to imaging technologies and services via the Italian Node (ALEMBIC, Milan-Italy). The Cell and Tissue Imaging (PICT-IBiSA) of the Institute Curie (ANR10-INBS-04). This work was supported by grants to CS: Italian Telethon Foundation (TCP12008), TIGEM institutional Grant, European Research Council (ERC) starting grant (714551), and Associazione Italiana per la Ricerca sul Cancro (A.I.R.C.) (IG 2015 Id 17717); MM: Signora Alessandra, AlphaONE Foundation, Foundation for Research on Neurodegenerative Diseases, the Novartis Foundation, Swiss National Science Foundation (SNF) and Comel and Gelu Foundations. To ID: DFG-funded Collaborative Research Centre on Selective Autophagy (SFB 1177), ERC no. 742720, DFG-funded SPP 1580 program and by the LOEWE program Ubiquitin Networks (Ub-Net) funded by the State of Hesse/Germany. Publisher Copyright: {\textcopyright} 2018 The Authors. Published under the terms of the CC BY 4.0 license",
year = "2019",
month = jan,
day = "15",
doi = "10.15252/embj.201899847",
language = "English",
volume = "38",
journal = "EMBO Journal",
issn = "0261-4189",
publisher = "EMBO Press",
number = "2",
}