title: Amino-terminal arginylation targets endoplasmic reticulum chaperone BiP for autophagy through p62 binding.
abstract: We show that ATE1-encoded Arg-transfer RNA transferase (R-transferase) of the N-end rule pathway mediates N-terminal arginylation of multiple endoplasmic reticulum (ER)-residing chaperones, leading to their cytosolic relocalization and turnover. N-terminal arginylation of BiP (also known as GRP78), protein disulphide isomerase and calreticulin is co-induced with autophagy during innate immune responses to cytosolic foreign DNA or proteasomal inhibition, associated with increased ubiquitylation. Arginylated BiP (R-BiP) is induced by and associated with cytosolic misfolded proteins destined for p62 (also known as sequestosome 1, SQSTM1) bodies. R-BiP binds the autophagic adaptor p62 through the interaction of its N-terminal arginine with the p62 ZZ domain. This allosterically induces self-oligomerization and aggregation of p62 and increases p62 interaction with LC3, leading to p62 targeting to autophagosomes and selective lysosomal co-degradation of R-BiP and p62 together with associated cargoes. In this autophagic mechanism, Nt-arginine functions as a delivery determinant, a degron and an activating ligand. Bioinformatics analysis predicts that many ER residents use arginylation to regulate non-ER processes.
authors.affiliation: World Class Institute, Korea Research Institute of Bioscience and Biotechnology, Ochang 363-883, Cheongwon, Korea.
authors.forename: Hyunjoo
authors.initials: H
authors.lastname: Cha-Molstad
authors.affiliation: 1] Protein Metabolism Medical Research Center and Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul 110-799, Korea [2] Center for Pharmacogenetics and Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.
authors.forename: Ki Sa
authors.initials: KS
authors.lastname: Sung
authors.affiliation: World Class Institute, Korea Research Institute of Bioscience and Biotechnology, Ochang 363-883, Cheongwon, Korea.
authors.forename: Joonsung
authors.initials: J
authors.lastname: Hwang
authors.affiliation: World Class Institute, Korea Research Institute of Bioscience and Biotechnology, Ochang 363-883, Cheongwon, Korea.
authors.forename: Kyoung A
authors.initials: KA
authors.lastname: Kim
authors.affiliation: 1] World Class Institute, Korea Research Institute of Bioscience and Biotechnology, Ochang 363-883, Cheongwon, Korea [2] Department of Drug Discovery and Development, College of Pharmacy, Chungbuk National University, Cheonju 361-736, Chungbuk, Korea.
authors.forename: Ji Eun
authors.initials: JE
authors.lastname: Yu
authors.affiliation: Protein Metabolism Medical Research Center and Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul 110-799, Korea.
authors.forename: Young Dong
authors.initials: YD
authors.lastname: Yoo
authors.affiliation: World Class University (WCU) Program, Department of Molecular Medicine and Biopharmaceutical Sciences, Seoul National University, Seoul 110-799, Korea.
authors.forename: Jun Min
authors.initials: JM
authors.lastname: Jang
authors.affiliation: Department of Applied Chemistry, College of Applied Sciences, Kyung Hee University, Yong-in 446-701, Korea.
authors.forename: Dong Hoon
authors.initials: DH
authors.lastname: Han
authors.affiliation: Protein Metabolism Medical Research Center and Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul 110-799, Korea.
authors.forename: Michael
authors.initials: M
authors.lastname: Molstad
authors.affiliation: World Class Institute, Korea Research Institute of Bioscience and Biotechnology, Ochang 363-883, Cheongwon, Korea.
authors.forename: Jung Gi
authors.initials: JG
authors.lastname: Kim
authors.affiliation: Protein Metabolism Medical Research Center and Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul 110-799, Korea.
authors.forename: Yoon Jee
authors.initials: YJ
authors.lastname: Lee
authors.affiliation: Center for Pharmacogenetics and Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.
authors.forename: Adriana
authors.initials: A
authors.lastname: Zakrzewska
authors.affiliation: World Class Institute, Korea Research Institute of Bioscience and Biotechnology, Ochang 363-883, Cheongwon, Korea.
authors.forename: Su-Hyeon
authors.initials: SH
authors.lastname: Kim
authors.affiliation: 1] Protein Metabolism Medical Research Center and Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul 110-799, Korea [2] Center for Pharmacogenetics and Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.
authors.forename: Sung Tae
authors.initials: ST
authors.lastname: Kim
authors.affiliation: Department of Otolaryngology, Ajou University School of Medicine, Suwon 443-380, Korea.
authors.forename: Sun Yong
authors.initials: SY
authors.lastname: Kim
authors.affiliation: Genomic Structure Research Center, Korea Research Institute of Bioscience and Biotechnology, Ochang 363-883, Cheongwon, Korea.
authors.forename: Hee Gu
authors.initials: HG
authors.lastname: Lee
authors.affiliation: World Class Institute, Korea Research Institute of Bioscience and Biotechnology, Ochang 363-883, Cheongwon, Korea.
authors.forename: Nak Kyun
authors.initials: NK
authors.lastname: Soung
authors.affiliation: Chemical Biology Research Center, Korea Research Institute of Bioscience and Biotechnology, Ochang 363-883, Cheongwon, Korea.
authors.forename: Jong Seog
authors.initials: JS
authors.lastname: Ahn
authors.affiliation: 1] Protein Metabolism Medical Research Center and Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul 110-799, Korea [2] The Polak Tumor and Vascular Biology Research Center, The Rappaport Faculty of Medicine and Research Institute, Technion-Israel Institute of Technology, Haifa 31096, Israel.
authors.forename: Aaron
authors.initials: A
authors.lastname: Ciechanover
authors.affiliation: World Class Institute, Korea Research Institute of Bioscience and Biotechnology, Ochang 363-883, Cheongwon, Korea.
authors.forename: Bo Yeon
authors.initials: BY
authors.lastname: Kim
authors.affiliation: 1] Protein Metabolism Medical Research Center and Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul 110-799, Korea [2] Ischemic/Hypoxic Disease Institute, College of Medicine, Seoul National University, Seoul 110-799, Korea.
authors.forename: Yong Tae
authors.initials: YT
authors.lastname: Kwon
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000595:Amino Acid Sequence; D019881:Aminoacyltransferases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001120:Arginine / Q000378:metabolism*; D001343:Autophagy; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000166:cytology; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D000091342:Endoplasmic Reticulum Chaperone BiP; D005347:Fibroblasts / Q000378:metabolism; D057809:HEK293 Cells; D006367:HeLa Cells; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D008969:Molecular Sequence Data; D011485:Protein Binding; D034622:RNA Interference; D017386:Sequence Homology, Amino Acid; D000071456:Sequestosome-1 Protein
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D008164:Luminescent Proteins; C477012:MAP1LC3A protein, human; D008869:Microtubule-Associated Proteins; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; D001120:Arginine; D019881:Aminoacyltransferases; C019727:arginyltransferase