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

Alison Forrester, Chiara De Leonibus, Paolo Grumati, Elisa Fasana, Marilina Piemontese, Leopoldo Staiano, Ilaria Fregno, Andrea Raimondi, Alessandro Marazza, Gemma Bruno, Maria Iavazzo, Daniela Intartaglia, Marta Seczynska, Eelco van Anken, Ivan Conte, Maria Antonietta De Matteis, Ivan Dikic, Maurizio Molinari, Carmine Settembre

Research output: Contribution to journalArticle

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.

Original languageEnglish
Article numbere99847
JournalEMBO Journal
Volume38
Issue number2
DOIs
Publication statusPublished - Jan 15 2019

Keywords

  • autophagy
  • Calnexin
  • collagen
  • endoplasmic reticulum
  • FAM134B

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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    Forrester, A., De Leonibus, C., Grumati, P., Fasana, E., Piemontese, M., Staiano, L., Fregno, I., Raimondi, A., Marazza, A., Bruno, G., Iavazzo, M., Intartaglia, D., Seczynska, M., van Anken, E., Conte, I., De Matteis, M. A., Dikic, I., Molinari, M., & Settembre, C. (2019). A selective ER-phagy exerts procollagen quality control via a Calnexin-FAM134B complex. EMBO Journal, 38(2), [e99847]. https://doi.org/10.15252/embj.201899847