caa a22 4500 569233208 CHVBK 20190802051658.0 cr unu---uuuuu 190724e20140801xx s 000 0 eng 10.1007/s00418-014-1204-3 doi 10.1007/s00418-014-1204-3 doi (NATIONALLICENCE)springer-10.1007/s00418-014-1204-3 (ZORA)oai:www.zora.uzh.ch:172013 570 ddc 610 ddc ERADication of EDEM1 occurs by selective autophagy and requires deglycosylation by cytoplasmic peptide N -glycanase [Elektronische Daten] [Sujin Park, Insook Jang, Christian Zuber, Yangsin Lee, Jin Cho, Ichiro Matsuo, Yukishige Ito, Jürgen Roth] openAccess eu-repo 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. Springer-Verlag Berlin Heidelberg, 2014 EDEM1 nationallicence Endoplasmic reticulum nationallicence Selective autophagy nationallicence Cytosolic peptide N -glycanase nationallicence LC3 nationallicence NBR1 nationallicence p62/SQSTM1 nationallicence Alfy nationallicence Alfy : Autophagy-linked FYVE protein nationallicence BODY-(GlcNAc)2-CIAc : Chloroacetamidyl chitobiose coupled to 4,4-difluoro-5,7-dimethyl-4-bora-3a,4a-diaza-s-indacene-3-propionic acid nationallicence PNGase : Cytoplasmic peptide N-glycanase nationallicence EDEM1 : ER degradation-enhancing α-mannosidase-like 1 protein nationallicence ER : Endoplasmic reticulum nationallicence ERAD : ER-associated protein degradation nationallicence LC3 : Microtubule-associated protein 1 light chain 3 beta nationallicence man : Mannose nationallicence GlcNAc : N-Acetylglucosamine nationallicence NBR1 : Neighbor of BRCA1 gene 1 nationallicence p62/SQSTM1 : Sequestosome 1 nationallicence siRNA : Short inhibitory RNA nationallicence Z-VAD(OMe)-fmk : Carbobenzyloxy-Val-Ala-Asp-α-fluoromethylketone nationallicence 142-005 zora Cell Biology, Molecular Biology, Medical Laboratory Technology, Histology zora Park Sujin WCU Program, Department of Integrated OMICS for Biomedical Science, Yonsei University Graduate School, 120-749, Seoul, Korea aut Jang Insook WCU Program, Department of Integrated OMICS for Biomedical Science, Yonsei University Graduate School, 120-749, Seoul, Korea aut Zuber Christian Division of Cell and Molecular Pathology, Department of Pathology, University of Zurich, 8091, Zurich, Switzerland aut Lee Yangsin WCU Program, Department of Integrated OMICS for Biomedical Science, Yonsei University Graduate School, 120-749, Seoul, Korea aut Cho Jin WCU Program, Department of Integrated OMICS for Biomedical Science, Yonsei University Graduate School, 120-749, Seoul, Korea aut Matsuo Ichiro Department of Chemistry and Chemical Biology, Gunma University, 376-8515, Maebashi, Gunma, Japan aut Ito Yukishige Synthetic Cellular Chemistry Laboratory, RIKEN, 351-0198, Wako, Saitama, Japan aut Roth Jürgen WCU Program, Department of Integrated OMICS for Biomedical Science, Yonsei University Graduate School, 120-749, Seoul, Korea aut Histochemistry and Cell Biology Springer Berlin Heidelberg 142/2(2014-08-01), 153-169 0948-6143 142:2<153 2014 142 418 https://doi.org/10.1007/s00418-014-1204-3 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s00418-014-1204-3 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Park Sujin WCU Program, Department of Integrated OMICS for Biomedical Science, Yonsei University Graduate School, 120-749, Seoul, Korea aut NATIONALLICENCE 700 1- Jang Insook WCU Program, Department of Integrated OMICS for Biomedical Science, Yonsei University Graduate School, 120-749, Seoul, Korea aut NATIONALLICENCE 700 1- Zuber Christian Division of Cell and Molecular Pathology, Department of Pathology, University of Zurich, 8091, Zurich, Switzerland aut NATIONALLICENCE 700 1- Lee Yangsin WCU Program, Department of Integrated OMICS for Biomedical Science, Yonsei University Graduate School, 120-749, Seoul, Korea aut NATIONALLICENCE 700 1- Cho Jin WCU Program, Department of Integrated OMICS for Biomedical Science, Yonsei University Graduate School, 120-749, Seoul, Korea aut NATIONALLICENCE 700 1- Matsuo Ichiro Department of Chemistry and Chemical Biology, Gunma University, 376-8515, Maebashi, Gunma, Japan aut NATIONALLICENCE 700 1- Ito Yukishige Synthetic Cellular Chemistry Laboratory, RIKEN, 351-0198, Wako, Saitama, Japan aut NATIONALLICENCE 700 1- Roth Jürgen WCU Program, Department of Integrated OMICS for Biomedical Science, Yonsei University Graduate School, 120-749, Seoul, Korea aut NATIONALLICENCE 773 0- Histochemistry and Cell Biology Springer Berlin Heidelberg 142/2(2014-08-01), 153-169 0948-6143 142:2<153 2014 142 418 ZORA 856 40 https://www.zora.uzh.ch/id/eprint/172013/1/ZORA_NL_172013.pdf text/html WWW-Backlink auf das Repository ZORA 700 1- Park Sujin joint author ZORA 700 1- Jang Insook joint author ZORA 700 1- Zuber Christian joint author ZORA 700 1- Lee Yangsin joint author ZORA 700 1- Cho Jin Won joint author ZORA 700 1- Matsuo Ichiro joint author ZORA 700 1- Ito Yukishige joint author ZORA 700 1- Roth Jürgen joint author ZORA 773 0- Histochemistry and Cell Biology 142(2):153-169 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer ZORA ZORA ZORA Journal Article openAccess