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ERADication of EDEM1 occurs by selective autophagy and requires deglycosylation by cytoplasmic peptide N -glycanase

Park, Sujin ; Jang, Insook ; Zuber, Christian ; Lee, Yangsin ; Cho, Jin ; Matsuo, Ichiro ; Ito, Yukishige ; Roth, Jürgen

In: Histochemistry and Cell Biology, 2014, vol. 142, no. 2, p. 153-169

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    Title
    • ERADication of EDEM1 occurs by selective autophagy and requires deglycosylation by cytoplasmic peptide N -glycanase
    Author
    • Park, Sujin. WCU Program, Department of Integrated OMICS for Biomedical Science, Yonsei University Graduate School, 120-749, Seoul, Korea
    • Jang, Insook. WCU Program, Department of Integrated OMICS for Biomedical Science, Yonsei University Graduate School, 120-749, Seoul, Korea
    • Zuber, Christian. Division of Cell and Molecular Pathology, Department of Pathology, University of Zurich, 8091, Zurich, Switzerland
    • Lee, Yangsin. WCU Program, Department of Integrated OMICS for Biomedical Science, Yonsei University Graduate School, 120-749, Seoul, Korea
    • Cho, Jin. WCU Program, Department of Integrated OMICS for Biomedical Science, Yonsei University Graduate School, 120-749, Seoul, Korea
    • Matsuo, Ichiro. Department of Chemistry and Chemical Biology, Gunma University, 376-8515, Maebashi, Gunma, Japan
    • Ito, Yukishige. Synthetic Cellular Chemistry Laboratory, RIKEN, 351-0198, Wako, Saitama, Japan
    • Roth, Jürgen. WCU Program, Department of Integrated OMICS for Biomedical Science, Yonsei University Graduate School, 120-749, Seoul, Korea
    Document Type
    • Postprint
    Language
    • English
    Published in
    • Histochemistry and Cell Biology, 2014, vol. 142, no. 2, p. 153-169. Springer Berlin Heidelberg
    Other Version
    OAI-PMH Identifier
    • oai:doc.rero.ch:326040
    Summary
    ER degradation-enhancing α-mannosidase-like 1 protein (EDEM1) is involved in the routing of misfolded glycoproteins for degradation in the cytoplasm. Previously, we reported that EDEM1 leaves the endoplasmic reticulum via non-COPII vesicles (Zuber et al. in Proc Natl Acad Sci USA 104:4407-4412, 2007) and becomes degraded by basal autophagy (Le Fourn et al. in Cell Mol Life Sci 66:1434-1445, 2009). However, it is unknown which type of autophagy is involved. Likewise, how EDEM1 is targeted to autophagosomes remains elusive. We now show that EDEM1 is degraded by selective autophagy. It colocalizes with the selective autophagy cargo receptors p62/SQSTM1, neighbor of BRCA1 gene 1 (NBR1) and autophagy-linked FYVE (Alfy) protein, and becomes engulfed by autophagic isolation membranes. The interaction with p62/SQSTM1 and NBR1 is required for routing of EDEM1 to autophagosomes since it can be blocked by short inhibitory RNA knockdown of the cargo receptors. Furthermore, p62/SQSTM1 interacts only with deglycosylated EDEM1 that is also ubiquitinated. The deglycosylation of EDEM1 occurs by the cytosolic peptide N-glycanase and is a prerequisite for interaction and aggregate formation with p62/SQSTM1 as demonstrated by the effect of peptide N-glycanase inhibitors on the formation of protein aggregates. Conversely, aggregation of p62/SQSTM1 and EDEM1 occurs independent of cytoplasmic histone deacetylase. These data provide novel insight into the mechanism of autophagic degradation of the ER-associated protein degradation (ERAD) component EDEM1 and disclose hitherto unknown parallels with the clearance of cytoplasmic aggregates of misfolded proteins by selective autophagy.