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[Article commentary]Modulation of SQSTM1/p62 activity by N-terminal arginylation of the endoplasmic reticulum chaperone HSPA5/GRP78/BiP
Hyunjoo Cha-Molstada† , Ji Eun Yuab† , Su Hyun Leec, Jung Gi Kima, Ki Sa Sungcd, Joonsung Hwanga, Young Dong Yooc, Yoon Jee Leec, Sung Tae Kimcd, Dae Hee Leee, Aaron Ciechanovercf, Bo Yeon Kima* & Yong Tae Kwoncg*

a World Class Institute, Korea Research Institute of Bioscience and Biotechnology, Ochang 363-883, Cheongwon, Korea.
b Department of Drug Discovery and Development, College of Pharmacy, Chungbuk National University, Cheongju 361-736, Chungbuk, Korea.
c Protein Metabolism Medical Research Center and Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul 110-799, Korea.
d Center for Pharmacogenetics and Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh Pittsburgh, PA 15261, 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 31096, Israel
g Ischemic/Hypoxic Disease Institute, College of Medicine, Seoul National University, Seoul 110-799, Korea.

*Corresponding authors
These authors have contributed equally.

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 protein disulfide isomerases. 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 SQSTM1self-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.

Key words : ATE1 R-transferase, N-end rule pathway, protein arginylation, protein quality control, proteolysis
논문정보
- 형식: Article commentary
- 게재일: 2016년 01월 (BRIC 등록일 2016-01-25)
- 연구진: 국내(교신)+국외 연구진태극기
- 분야: Cell_Biology
Dot/Icm 제 4 유형 커플링 단백질 복합체의 선택적 이펙터 단백질 인식[Nat. Commun.]
김현민
발표: 김현민 (KAIST)
일자: 2020년 9월 29일 (화) 오후 02시 (한국시간)
언어: 한국어
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