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Nat Commun. 2017 Jul 24;8(1):102. doi: 10.1038/s41467-017-00085-7.

p62/SQSTM1/Sequestosome-1 is an N-recognin of the N-end rule pathway which modulates autophagosome biogenesis.

Cha-Molstad H1, Yu JE1,2, Feng Z3,4,5,6, Lee SH7, Kim JG1,8, Yang P3,4,5,6, Han B9, Sung KW7, Yoo YD7, Hwang J1, McGuire T3,4,5,6, Shim SM7, Song HD10, Ganipisetti S1, Wang N3,4,5,6, Jang JM7,11, Lee MJ12, Kim SJ13, Lee KH1, Hong JT2, Ciechanover A7,14, Mook-Jung I10, Kim KP9, Xie XQ15,16,17,18, Kwon YT19,20, Kim BY21,22.

Author information

1
World Class Institute, Anticancer Agents Research Center, Korea Research Institute of Bioscience and Biotechnology, Ochang, Cheongwon, 28116, Korea.
2
Department of Drug Discovery and Development, College of Pharmacy, Chungbuk National University, Chungbuk, Cheongju, 28644, Korea.
3
Department of Pharmaceutical Sciences and Computational Chemical Genomics Screening Center, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, 15260, USA.
4
NIDA National Center of Excellence for Computational Drug Abuse Research, University of Pittsburgh, Pittsburgh, PA, 15260, USA.
5
Drug Discovery Institute, University of Pittsburgh, Pittsburgh, PA, 15260, USA.
6
Departments of Computational Biology and Structural Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, 15260, USA.
7
Protein Metabolism Medical Research Center and Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul, 03080, Korea.
8
Department of Biomolecular Science, University of Science and Technology (UST), Daejeon, 34113, South Korea.
9
Department of Applied Chemistry, College of Applied Science, Kyung Hee University, Yongin, 17104, Korea.
10
Department of Biochemistry and Biomedical Science, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea.
11
QC Team Operation Part Sample Managements, Samsung Biologics, Yeonsu-gu, Incheon, 21987, Korea.
12
Department of Biochemistry and Molecular Biology, Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea.
13
Disease Target Structure Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, 34141, Korea.
14
Technion Integrated Cancer Center (TICC), Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, 31096, Israel.
15
Department of Pharmaceutical Sciences and Computational Chemical Genomics Screening Center, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, 15260, USA. xix15@pitt.edu.
16
NIDA National Center of Excellence for Computational Drug Abuse Research, University of Pittsburgh, Pittsburgh, PA, 15260, USA. xix15@pitt.edu.
17
Drug Discovery Institute, University of Pittsburgh, Pittsburgh, PA, 15260, USA. xix15@pitt.edu.
18
Departments of Computational Biology and Structural Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, 15260, USA. xix15@pitt.edu.
19
Protein Metabolism Medical Research Center and Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul, 03080, Korea. yok5@snu.ac.kr.
20
Ischemic/Hypoxic Disease Institute, College of Medicine, Seoul National University, Seoul, 03080, Korea. yok5@snu.ac.kr.
21
World Class Institute, Anticancer Agents Research Center, Korea Research Institute of Bioscience and Biotechnology, Ochang, Cheongwon, 28116, Korea. bykim@kribb.re.kr.
22
Department of Biomolecular Science, University of Science and Technology (UST), Daejeon, 34113, South Korea. bykim@kribb.re.kr.

Abstract

Macroautophagy mediates the selective degradation of proteins and non-proteinaceous cellular constituents. Here, we show that the N-end rule pathway modulates macroautophagy. In this mechanism, the autophagic adapter p62/SQSTM1/Sequestosome-1 is an N-recognin that binds type-1 and type-2 N-terminal degrons (N-degrons), including arginine (Nt-Arg). Both types of N-degrons bind its ZZ domain. By employing three-dimensional modeling, we developed synthetic ligands to p62 ZZ domain. The binding of Nt-Arg and synthetic ligands to ZZ domain facilitates disulfide bond-linked aggregation of p62 and p62 interaction with LC3, leading to the delivery of p62 and its cargoes to the autophagosome. Upon binding to its ligand, p62 acts as a modulator of macroautophagy, inducing autophagosome biogenesis. Through these dual functions, cells can activate p62 and induce selective autophagy upon the accumulation of autophagic cargoes. We also propose that p62 mediates the crosstalk between the ubiquitin-proteasome system and autophagy through its binding Nt-Arg and other N-degrons.Soluble misfolded proteins that fail to be degraded by the ubiquitin proteasome system (UPS) are redirected to autophagy via specific adaptors, such as p62. Here the authors show that p62 recognises N-degrons in these proteins, acting as a N-recognin from the proteolytic N-end rule pathway, and targets these cargos to autophagosomal degradation.

PMID:
28740232
PMCID:
PMC5524641
DOI:
10.1038/s41467-017-00085-7
[Indexed for MEDLINE]
Free PMC Article

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