Hyunjoo Cha-Molstad1,12, Ki Sa Sung2,3,12, Joonsung Hwang1,12, Kyoung A. Kim1,12, Ji Eun Yu1,4, Young Dong Yoo2, JunMin Jang5,13, Dong Hoon Han6,MichaelMolstad2, Jung Gi Kim1, Yoon Jee Lee2, Adriana Zakrzewska3, Su-Hyeon Kim1, Sung Tae Kim2,3, Sun Yong Kim7, Hee Gu Lee8, Nak Kyun Soung1, Jong Seog Ahn9, Aaron Ciechanover2,10, Bo Yeon Kim1,14 and Yong Tae Kwon2,11,14
1World Class Institute, Korea Research Institute of Bioscience and Biotechnology, Ochang 363-883, Cheongwon, Korea. 2Protein Metabolism Medical Research Center and Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul 110-799, Korea. 3Center for Pharmacogenetics and Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA. 4Department of Drug Discovery and Development, College of Pharmacy, Chungbuk National University, Cheonju 361-736, Chungbuk, Korea. 5World Class University (WCU) Program, Department of Molecular Medicine and Biopharmaceutical Sciences, Seoul National University, Seoul 110-799, Korea. 6Department of Applied Chemistry, College of Applied Sciences, Kyung Hee University, Yong-in 446-701, Korea. 7Department of Otolaryngology, Ajou University School of Medicine, Suwon 443-380, Korea. 8Genomic Structure Research Center, Korea Research Institute of Bioscience and Biotechnology, Ochang 363-883, Cheongwon, Korea. 9Chemical Biology Research Center, Korea Research Institute of Bioscience and Biotechnology, Ochang 363-883, Cheongwon, Korea. 10The Polak Tumor and Vascular Biology Research Center, The Rappaport Faculty of Medicine and Research Institute, Technion-Israel Institute of Technology, Haifa 31096, Israel. 11Ischemic/Hypoxic Disease Institute, College of Medicine, Seoul National University, Seoul 110-799, Korea. 12These authors contributed equally to this work. 13Present address: Quality Control Division, Yuhan Chemical, Ansan, Kyung Kee 425-836, Korea.
14Correspondence should be addressed to Bo Yeon Kim or Yong Tae Kwon
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.