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

Author

Listed:
  • Hyunjoo Cha-Molstad

    (Korea Research Institute of Bioscience and Biotechnology)

  • Ji Eun Yu

    (Korea Research Institute of Bioscience and Biotechnology
    Chungbuk National University)

  • Zhiwei Feng

    (University of Pittsburgh
    University of Pittsburgh
    University of Pittsburgh
    University of Pittsburgh)

  • Su Hyun Lee

    (Seoul National University)

  • Jung Gi Kim

    (Korea Research Institute of Bioscience and Biotechnology
    University of Science and Technology (UST))

  • Peng Yang

    (University of Pittsburgh
    University of Pittsburgh
    University of Pittsburgh
    University of Pittsburgh)

  • Bitnara Han

    (Kyung Hee University)

  • Ki Woon Sung

    (Seoul National University)

  • Young Dong Yoo

    (Seoul National University)

  • Joonsung Hwang

    (Korea Research Institute of Bioscience and Biotechnology)

  • Terry McGuire

    (University of Pittsburgh
    University of Pittsburgh
    University of Pittsburgh
    University of Pittsburgh)

  • Sang Mi Shim

    (Seoul National University)

  • Hyun Dong Song

    (Seoul National University College of Medicine)

  • Srinivasrao Ganipisetti

    (Korea Research Institute of Bioscience and Biotechnology)

  • Nuozhou Wang

    (University of Pittsburgh
    University of Pittsburgh
    University of Pittsburgh
    University of Pittsburgh)

  • Jun Min Jang

    (Seoul National University
    Samsung Biologics)

  • Min Jae Lee

    (Seoul National University College of Medicine)

  • Seung Jun Kim

    (Korea Research Institute of Bioscience and Biotechnology)

  • Kyung Ho Lee

    (Korea Research Institute of Bioscience and Biotechnology)

  • Jin Tae Hong

    (Chungbuk National University)

  • Aaron Ciechanover

    (Seoul National University
    Technion-Israel Institute of Technology)

  • Inhee Mook-Jung

    (Seoul National University College of Medicine)

  • Kwang Pyo Kim

    (Kyung Hee University)

  • Xiang-Qun Xie

    (University of Pittsburgh
    University of Pittsburgh
    University of Pittsburgh
    University of Pittsburgh)

  • Yong Tae Kwon

    (Seoul National University
    Seoul National University)

  • Bo Yeon Kim

    (Korea Research Institute of Bioscience and Biotechnology
    University of Science and Technology (UST))

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.

Suggested Citation

  • Hyunjoo Cha-Molstad & Ji Eun Yu & Zhiwei Feng & Su Hyun Lee & Jung Gi Kim & Peng Yang & Bitnara Han & Ki Woon Sung & Young Dong Yoo & Joonsung Hwang & Terry McGuire & Sang Mi Shim & Hyun Dong Song & S, 2017. "p62/SQSTM1/Sequestosome-1 is an N-recognin of the N-end rule pathway which modulates autophagosome biogenesis," Nature Communications, Nature, vol. 8(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-00085-7
    DOI: 10.1038/s41467-017-00085-7
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    Cited by:

    1. Chang Hoon Ji & Hee Yeon Kim & Min Ju Lee & Ah Jung Heo & Daniel Youngjae Park & Sungsu Lim & Seulgi Shin & Srinivasrao Ganipisetti & Woo Seung Yang & Chang An Jung & Kun Young Kim & Eun Hye Jeong & S, 2022. "The AUTOTAC chemical biology platform for targeted protein degradation via the autophagy-lysosome system," Nature Communications, Nature, vol. 13(1), pages 1-14, December.

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