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Local membrane source gathering by p62 body drives autophagosome formation

Author

Listed:
  • Xuezhao Feng

    (The First Affiliated Hospital of Xinjiang Medical University
    Xinjiang Medical University)

  • Daxiao Sun

    (Max Planck Institute of Molecular Cell Biology and Genetics)

  • Yanchang Li

    (Beijing Proteome Research Center, Institute of Lifeomics)

  • Jinpei Zhang

    (The First Affiliated Hospital of Xinjiang Medical University
    Xinjiang Medical University)

  • Shiyu Liu

    (The First Affiliated Hospital of Xinjiang Medical University
    Xinjiang Medical University)

  • Dachuan Zhang

    (Tsinghua University)

  • Jingxiang Zheng

    (Tsinghua University)

  • Qing Xi

    (The First Affiliated Hospital of Xinjiang Medical University
    Xinjiang Medical University)

  • Haisha Liang

    (Tsinghua University)

  • Wenkang Zhao

    (Tsinghua University)

  • Ying Li

    (Tsinghua University)

  • Mengbo Xu

    (The First Affiliated Hospital of Xinjiang Medical University
    Xinjiang Medical University)

  • Jiayu He

    (The First Affiliated Hospital of Xinjiang Medical University
    Xinjiang Medical University)

  • Tong Liu

    (The First Affiliated Hospital of Xinjiang Medical University
    Xinjiang Medical University)

  • Ayshamgul Hasim

    (Xinjiang Medical University
    Xinjiang Medical University)

  • Meisheng Ma

    (Tongji Medical College of Huazhong University of Science and Technology)

  • Ping Xu

    (Beijing Proteome Research Center, Institute of Lifeomics)

  • Na Mi

    (The First Affiliated Hospital of Xinjiang Medical University
    Xinjiang Medical University
    Key Laboratory of High Incidence Disease Research in Xinjiang (Xinjiang Medical University), Ministry of Education)

Abstract

Autophagosomes are double-membrane vesicles generated intracellularly to encapsulate substrates for lysosomal degradation during autophagy. Phase separated p62 body plays pivotal roles during autophagosome formation, however, the underlying mechanisms are still not fully understood. Here we describe a spatial membrane gathering mode by which p62 body functions in autophagosome formation. Mass spectrometry-based proteomics reveals significant enrichment of vesicle trafficking components within p62 body. Combining cellular experiments and biochemical reconstitution assays, we confirm the gathering of ATG9 and ATG16L1-positive vesicles around p62 body, especially in Atg2ab DKO cells with blocked lipid transfer and vesicle fusion. Interestingly, p62 body also regulates ATG9 and ATG16L vesicle trafficking flux intracellularly. We further determine the lipid contents associated with p62 body via lipidomic profiling. Moreover, with in vitro kinase assay, we uncover the functions of p62 body as a platform to assemble ULK1 complex and invigorate PI3KC3-C1 kinase cascade for PI3P generation. Collectively, our study raises a membrane-based working model for multifaceted p62 body in controlling autophagosome biogenesis, and highlights the interplay between membraneless condensates and membrane vesicles in regulating cellular functions.

Suggested Citation

  • Xuezhao Feng & Daxiao Sun & Yanchang Li & Jinpei Zhang & Shiyu Liu & Dachuan Zhang & Jingxiang Zheng & Qing Xi & Haisha Liang & Wenkang Zhao & Ying Li & Mengbo Xu & Jiayu He & Tong Liu & Ayshamgul Has, 2023. "Local membrane source gathering by p62 body drives autophagosome formation," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-42829-8
    DOI: 10.1038/s41467-023-42829-8
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    References listed on IDEAS

    as
    1. Eleonora Turco & Adriana Savova & Flora Gere & Luca Ferrari & Julia Romanov & Martina Schuschnig & Sascha Martens, 2021. "Reconstitution defines the roles of p62, NBR1 and TAX1BP1 in ubiquitin condensate formation and autophagy initiation," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
    2. Zhiyuan You & Wen-Xue Jiang & Ling-Yun Qin & Zhou Gong & Wei Wan & Jin Li & Yusha Wang & Hongtao Zhang & Chao Peng & Tianhua Zhou & Chun Tang & Wei Liu, 2019. "Requirement for p62 acetylation in the aggregation of ubiquitylated proteins under nutrient stress," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
    3. Shun Kageyama & Sigurdur Runar Gudmundsson & Yu-Shin Sou & Yoshinobu Ichimura & Naoki Tamura & Saiko Kazuno & Takashi Ueno & Yoshiki Miura & Daisuke Noshiro & Manabu Abe & Tsunehiro Mizushima & Nobuak, 2021. "p62/SQSTM1-droplet serves as a platform for autophagosome formation and anti-oxidative stress response," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
    4. Jaime Agudo-Canalejo & Sebastian W. Schultz & Haruka Chino & Simona M. Migliano & Chieko Saito & Ikuko Koyama-Honda & Harald Stenmark & Andreas Brech & Alexander I. May & Noboru Mizushima & Roland L. , 2021. "Wetting regulates autophagy of phase-separated compartments and the cytosol," Nature, Nature, vol. 591(7848), pages 142-146, March.
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