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p62/SQSTM1/Sequestosome-1 is an N-recognin of the N-end rule pathway which modulates autophagosome biogenesis.
Cha-Molstad, Hyunjoo; Yu, Ji Eun; Feng, Zhiwei; Lee, Su Hyun; Kim, Jung Gi; Yang, Peng; Han, Bitnara; Sung, Ki Woon; Yoo, Young Dong; Hwang, Joonsung; McGuire, Terry; Shim, Sang Mi; Song, Hyun Dong; Ganipisetti, Srinivasrao; Wang, Nuozhou; Jang, Jun Min; Lee, Min Jae; Kim, Seung Jun; Lee, Kyung Ho; Hong, Jin Tae; Ciechanover, Aaron; Mook-Jung, Inhee; Kim, Kwang Pyo; Xie, Xiang-Qun; Kwon, Yong Tae; Kim, Bo Yeon.
Afiliación
  • Cha-Molstad H; World Class Institute, Anticancer Agents Research Center, Korea Research Institute of Bioscience and Biotechnology, Ochang, Cheongwon, 28116, Korea.
  • Yu JE; World Class Institute, Anticancer Agents Research Center, Korea Research Institute of Bioscience and Biotechnology, Ochang, Cheongwon, 28116, Korea.
  • Feng Z; Department of Drug Discovery and Development, College of Pharmacy, Chungbuk National University, Chungbuk, Cheongju, 28644, Korea.
  • Lee SH; Department of Pharmaceutical Sciences and Computational Chemical Genomics Screening Center, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, 15260, USA.
  • Kim JG; NIDA National Center of Excellence for Computational Drug Abuse Research, University of Pittsburgh, Pittsburgh, PA, 15260, USA.
  • Yang P; Drug Discovery Institute, University of Pittsburgh, Pittsburgh, PA, 15260, USA.
  • Han B; Departments of Computational Biology and Structural Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, 15260, USA.
  • Sung KW; Protein Metabolism Medical Research Center and Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul, 03080, Korea.
  • Yoo YD; World Class Institute, Anticancer Agents Research Center, Korea Research Institute of Bioscience and Biotechnology, Ochang, Cheongwon, 28116, Korea.
  • Hwang J; Department of Biomolecular Science, University of Science and Technology (UST), Daejeon, 34113, South Korea.
  • McGuire T; Department of Pharmaceutical Sciences and Computational Chemical Genomics Screening Center, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, 15260, USA.
  • Shim SM; NIDA National Center of Excellence for Computational Drug Abuse Research, University of Pittsburgh, Pittsburgh, PA, 15260, USA.
  • Song HD; Drug Discovery Institute, University of Pittsburgh, Pittsburgh, PA, 15260, USA.
  • Ganipisetti S; Departments of Computational Biology and Structural Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, 15260, USA.
  • Wang N; Department of Applied Chemistry, College of Applied Science, Kyung Hee University, Yongin, 17104, Korea.
  • Jang JM; Protein Metabolism Medical Research Center and Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul, 03080, Korea.
  • Lee MJ; Protein Metabolism Medical Research Center and Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul, 03080, Korea.
  • Kim SJ; World Class Institute, Anticancer Agents Research Center, Korea Research Institute of Bioscience and Biotechnology, Ochang, Cheongwon, 28116, Korea.
  • Lee KH; Department of Pharmaceutical Sciences and Computational Chemical Genomics Screening Center, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, 15260, USA.
  • Hong JT; NIDA National Center of Excellence for Computational Drug Abuse Research, University of Pittsburgh, Pittsburgh, PA, 15260, USA.
  • Ciechanover A; Drug Discovery Institute, University of Pittsburgh, Pittsburgh, PA, 15260, USA.
  • Mook-Jung I; Departments of Computational Biology and Structural Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, 15260, USA.
  • Kim KP; Protein Metabolism Medical Research Center and Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul, 03080, Korea.
  • Xie XQ; Department of Biochemistry and Biomedical Science, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea.
  • Kwon YT; World Class Institute, Anticancer Agents Research Center, Korea Research Institute of Bioscience and Biotechnology, Ochang, Cheongwon, 28116, Korea.
  • Kim BY; Department of Pharmaceutical Sciences and Computational Chemical Genomics Screening Center, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, 15260, USA.
Nat Commun ; 8(1): 102, 2017 07 24.
Article en En | MEDLINE | ID: mdl-28740232
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Transducción de Señal / Autofagosomas / Proteína Sequestosoma-1 / Proteínas Asociadas a Microtúbulos Límite: Animals / Humans Idioma: En Revista: Nat Commun Asunto de la revista: BIOLOGIA / CIENCIA Año: 2017 Tipo del documento: Article Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Transducción de Señal / Autofagosomas / Proteína Sequestosoma-1 / Proteínas Asociadas a Microtúbulos Límite: Animals / Humans Idioma: En Revista: Nat Commun Asunto de la revista: BIOLOGIA / CIENCIA Año: 2017 Tipo del documento: Article Pais de publicación: Reino Unido