title: Modulation of SQSTM1/p62 activity by N-terminal arginylation of the endoplasmic reticulum chaperone HSPA5/GRP78/BiP.
abstract: The N-end rule pathway is a proteolytic system, in which single N-terminal residues act as a determinant of a class of degrons, called N-degrons. In the ubiquitin (Ub)-proteasome system, specific recognition components, called N-recognins, recognize N-degrons and accelerate polyubiquitination and proteasomal degradation of the substrates. In this study, we show that the pathway regulates the activity of the macroautophagic receptor SQSTM1/p62 (sequestosome 1) through N-terminal arginylation (Nt-arginylation) of endoplasmic reticulum (ER)-residing molecular chaperones, including HSPA5/GRP78/BiP, CALR (calreticulin), and PDI (protein disulfide isomerase). The arginylation is co-induced with macroautophagy (hereafter autophagy) as part of innate immunity to cytosolic DNA and when misfolded proteins accumulate under proteasomal inhibition. Following cytosolic relocalization and arginylation, Nt-arginylated HSPA5 (R-HSPA5) is targeted to autophagosomes and degraded by lysosomal hydrolases through the interaction of its N-terminal Arg (Nt-Arg) with ZZ domain of SQSTM1. Upon binding to Nt-Arg, SQSTM1 undergoes a conformational change, which promotes SQSTM1 self-polymerization and interaction with LC3, leading to SQSTM1 targeting to autophagosomes. Cargoes of R-HSPA5 include cytosolic misfolded proteins destined to be degraded through autophagy. Here, we discuss the mechanisms by which the N-end rule pathway regulates SQSTM1-dependent selective autophagy.
authors.affiliation: a World Class Institute, Korea Research Institute of Bioscience and Biotechnology , Ochang , Cheongwon , Korea.
authors.forename: Hyunjoo
authors.initials: H
authors.lastname: Cha-Molstad
authors.affiliation: a World Class Institute, Korea Research Institute of Bioscience and Biotechnology , Ochang , Cheongwon , Korea.|b Department of Drug Discovery and Development , College of Pharmacy, Chungbuk National University , Cheongju , Chungbuk , Korea.
authors.forename: Ji Eun
authors.initials: JE
authors.lastname: Yu
authors.affiliation: c Protein Metabolism Medical Research Center and Department of Biomedical Sciences, College of Medicine, Seoul National University , Seoul , Korea.
authors.forename: Su Hyun
authors.initials: SH
authors.lastname: Lee
authors.affiliation: a World Class Institute, Korea Research Institute of Bioscience and Biotechnology , Ochang , Cheongwon , Korea.
authors.forename: Jung Gi
authors.initials: JG
authors.lastname: Kim
authors.affiliation: c Protein Metabolism Medical Research Center and Department of Biomedical Sciences, College of Medicine, Seoul National University , Seoul , Korea.|d Center for Pharmacogenetics and Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh Pittsburgh , PA , USA.
authors.forename: Ki Sa
authors.initials: KS
authors.lastname: Sung
authors.affiliation: a World Class Institute, Korea Research Institute of Bioscience and Biotechnology , Ochang , Cheongwon , Korea.
authors.forename: Joonsung
authors.initials: J
authors.lastname: Hwang
authors.affiliation: a World Class Institute, Korea Research Institute of Bioscience and Biotechnology , Ochang , Cheongwon , Korea.|c Protein Metabolism Medical Research Center and Department of Biomedical Sciences, College of Medicine, Seoul National University , Seoul , Korea.
authors.forename: Young Dong
authors.initials: YD
authors.lastname: Yoo
authors.affiliation: c Protein Metabolism Medical Research Center and Department of Biomedical Sciences, College of Medicine, Seoul National University , Seoul , Korea.
authors.forename: Yoon Jee
authors.initials: YJ
authors.lastname: Lee
authors.affiliation: c Protein Metabolism Medical Research Center and Department of Biomedical Sciences, College of Medicine, Seoul National University , Seoul , Korea.|d Center for Pharmacogenetics and Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh Pittsburgh , PA , USA.
authors.forename: Sung Tae
authors.initials: ST
authors.lastname: Kim
authors.affiliation: e Division of Oncology/Hematology , Department of Internal Medicine, Korea University College of Medicine , Seoul , Republic of Korea.
authors.forename: Dae Hee
authors.initials: DH
authors.lastname: Lee
authors.affiliation: c Protein Metabolism Medical Research Center and Department of Biomedical Sciences, College of Medicine, Seoul National University , Seoul , Korea.|f The Polak Tumor and Vascular Biology Research Center, The Rappaport Faculty of Medicine and Research Institute, Technion-Israel Institute of Technology , Haifa , Israel.
authors.forename: Aaron
authors.initials: A
authors.lastname: Ciechanover
authors.affiliation: a World Class Institute, Korea Research Institute of Bioscience and Biotechnology , Ochang , Cheongwon , Korea.
authors.forename: Bo Yeon
authors.initials: BY
authors.lastname: Kim
authors.affiliation: c Protein Metabolism Medical Research Center and Department of Biomedical Sciences, College of Medicine, Seoul National University , Seoul , Korea.|g Ischemic/Hypoxic Disease Institute, College of Medicine, Seoul National University , Seoul , Korea.
authors.forename: Yong Tae
authors.initials: YT
authors.lastname: Kwon
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D001120:Arginine / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D008954:Models, Biological; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D059748:Proteolysis; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; D025801:Ubiquitin; D001120:Arginine; D046988:Proteasome Endopeptidase Complex
keywords: ATE1 R-transferase; N-end rule pathway; protein arginylation; protein quality control; proteolysis