Format

Send to

Choose Destination
EMBO J. 2019 Jan 15;38(2). pii: e99847. doi: 10.15252/embj.201899847. Epub 2018 Dec 17.

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

Author information

1
Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy.
2
Institute of Biochemistry II, Goethe University Frankfurt - Medical Faculty, University Hospital, Frankfurt am Main, Germany.
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
Experimental Imaging Center, San Raffaele Scientific Institute, Milan, Italy.
6
Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland.
7
Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Ospedale San Raffaele, Milan, Italy.
8
Department of Molecular Medicine and Medical Biotechnologies, University of Naples "Federico II", Naples, Italy.
9
Institute of Biochemistry II, Goethe University Frankfurt - Medical Faculty, University Hospital, Frankfurt am Main, Germany dikic@biochem2.uni-frankfurt.de maurizio.molinari@irb.usi.ch settembre@tigem.it.
10
Buchmann Institute for Molecular Life Sciences, Goethe University Frankfurt, Frankfurt am Main, Germany.
11
Faculty of Biomedical Sciences, Institute for Research in Biomedicine, Università della Svizzera italiana (USI), Bellinzona, Switzerland dikic@biochem2.uni-frankfurt.de maurizio.molinari@irb.usi.ch settembre@tigem.it.
12
School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
13
Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy dikic@biochem2.uni-frankfurt.de maurizio.molinari@irb.usi.ch settembre@tigem.it.
14
Department of Medical and Translational Science, University of Naples "Federico II", Naples, Italy.

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:

Calnexin; FAM134B; autophagy; collagen; endoplasmic reticulum

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center