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Autophagy. 2016;12(2):426-8. doi: 10.1080/15548627.2015.1126047.

Modulation of SQSTM1/p62 activity by N-terminal arginylation of the endoplasmic reticulum chaperone HSPA5/GRP78/BiP.

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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.
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.
e Division of Oncology/Hematology , Department of Internal Medicine, Korea University College of Medicine , Seoul , Republic of 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.
g Ischemic/Hypoxic Disease Institute, College of Medicine, Seoul National University , Seoul , Korea.


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.


ATE1 R-transferase; N-end rule pathway; protein arginylation; protein quality control; proteolysis

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