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

被引：195

作者：

Forrester, Alison ^{[1
]}

De Leonibus, Chiara ^{[1
]}

Grumati, Paolo ^{[2
]}

Fasana, Elisa ^{[3
]}

Piemontese, Marilina ^{[1
]}

Staiano, Leopoldo ^{[1
]}

Fregno, Ilaria ^{[3
,4
]}

Raimondi, Andrea ^{[5
]}

Marazza, Alessandro ^{[3
,6
]}

Bruno, Gemma ^{[1
]}

Iavazzo, Maria ^{[1
]}

Intartaglia, Daniela ^{[1
]}

Seczynska, Marta ^{[2
]}

van Anken, Eelco ^{[7
]}

Conte, Ivan ^{[1
]}

De Matteis, Maria Antonietta ^{[1
,8
]}

Dikic, Ivan ^{[2
,9
]}

Molinari, Maurizio ^{[3
,10
]}

Settembre, Carmine ^{[1
,11
]}

机构：

[1] Telethon Inst Genet & Med TIGEM, Pozzuoli, Italy

[2] Goethe Univ Frankfurt, Univ Hosp, Inst Biochem 2, Med Fac, Frankfurt, Germany

[3] USI, Inst Res Biomed, Fac Biomed Sci, Bellinzona, Switzerland

[4] Swiss Fed Inst Technol, Dept Biol, Zurich, Switzerland

[5] Ist Sci San Raffaele, Expt Imaging Ctr, Milan, Italy

[6] Univ Bern, Grad Sch Cellular & Biomed Sci, Bern, Switzerland

[7] Osped San Raffaele, San Raffaele Sci Inst, Div Genet & Cell Biol, Milan, Italy

[8] Univ Naples Federico II, Dept Mol Med & Med Biotechnol, Naples, Italy

[9] Goethe Univ Frankfurt, Buchmann Inst Mol Life Sci, Frankfurt, Germany

[10] Ecole Polytech Fed Lausanne, Sch Life Sci, Lausanne, Switzerland

[11] Univ Naples Federico II, Dept Med & Translat Sci, Naples, Italy

来源：

EMBO JOURNAL | 2019年 / 38卷 / 02期

基金：

瑞士国家科学基金会; 欧洲研究理事会;

关键词：

autophagy; Calnexin; collagen; endoplasmic reticulum; FAM134B; ENDOPLASMIC-RETICULUM TURNOVER; AUTOPHAGY DEGRADES; BONE-GROWTH; DEGRADATION; RECEPTOR; CALRETICULIN; ASSOCIATION; SUBUNIT; LECTINS; PATHWAY;

D O I：

10.15252/embj.201899847

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页数：16

共 49 条

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