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Wetting regulates autophagy of phase-separated compartments and the cytosol

Author

Listed:
  • Jaime Agudo-Canalejo

    (University of Oxford
    The Pennsylvania State University
    Max Planck Institute for Dynamics and Self-Organization)

  • Sebastian W. Schultz

    (Oslo University Hospital
    University of Oslo)

  • Haruka Chino

    (The University of Tokyo)

  • Simona M. Migliano

    (Oslo University Hospital
    University of Oslo)

  • Chieko Saito

    (The University of Tokyo)

  • Ikuko Koyama-Honda

    (The University of Tokyo)

  • Harald Stenmark

    (Oslo University Hospital
    University of Oslo)

  • Andreas Brech

    (Oslo University Hospital
    University of Oslo)

  • Alexander I. May

    (Tokyo Institute of Technology
    Tokyo Institute of Technology)

  • Noboru Mizushima

    (The University of Tokyo)

  • Roland L. Knorr

    (The University of Tokyo
    Max Planck Institute of Colloids and Interfaces
    Max Planck Institute of Molecular Plant Physiology)

Abstract

Compartmentalization of cellular material in droplet-like structures is a hallmark of liquid–liquid phase separation1,2, but the mechanisms of droplet removal are poorly understood. Evidence suggests that droplets can be degraded by autophagy3,4, a highly conserved degradation system in which membrane sheets bend to isolate portions of the cytoplasm within double-membrane autophagosomes5–7. Here we examine how autophagosomes sequester droplets that contain the protein p62 (also known as SQSTM1) in living cells, and demonstrate that double-membrane, autophagosome-like vesicles form at the surface of protein-free droplets in vitro through partial wetting. A minimal physical model shows that droplet surface tension supports the formation of membrane sheets. The model also predicts that bending sheets either divide droplets for piecemeal sequestration or sequester entire droplets. We find that autophagosomal sequestration is robust to variations in the droplet-sheet adhesion strength. However, the two sides of partially wetted sheets are exposed to different environments, which can determine the bending direction of autophagosomal sheets. Our discovery of this interplay between the material properties of droplets and membrane sheets enables us to elucidate the mechanisms that underpin droplet autophagy, or ‘fluidophagy’. Furthermore, we uncover a switching mechanism that allows droplets to act as liquid assembly platforms for cytosol-degrading autophagosomes8 or as specific autophagy substrates9–11. We propose that droplet-mediated autophagy represents a previously undescribed class of processes that are driven by elastocapillarity, highlighting the importance of wetting in cytosolic organization.

Suggested Citation

  • 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.
  • Handle: RePEc:nat:nature:v:591:y:2021:i:7848:d:10.1038_s41586-020-2992-3
    DOI: 10.1038/s41586-020-2992-3
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    Citations

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    Cited by:

    1. David M. Hollenstein & Mariya Licheva & Nicole Konradi & David Schweida & Hector Mancilla & Muriel Mari & Fulvio Reggiori & Claudine Kraft, 2021. "Spatial control of avidity regulates initiation and progression of selective autophagy," Nature Communications, Nature, vol. 12(1), pages 1-18, December.
    2. Xi Li & Linwei Yu & Xikai Liu & Tianyi Shi & Yu Zhang & Yushuo Xiao & Chen Wang & Liangliang Song & Ning Li & Xinran Liu & Yuchen Chen & Robert B. Petersen & Xiang Cheng & Weikang Xue & Yanxun V. Yu &, 2024. "β-synuclein regulates the phase transitions and amyloid conversion of α-synuclein," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    3. Ling-Gang Wu & Chung Yu Chan, 2024. "Membrane transformations of fusion and budding," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    4. 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.
    5. Dinesh Sundaravadivelu Devarajan & Jiahui Wang & Beata Szała-Mendyk & Shiv Rekhi & Arash Nikoubashman & Young C. Kim & Jeetain Mittal, 2024. "Sequence-dependent material properties of biomolecular condensates and their relation to dilute phase conformations," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    6. Agustín Mangiarotti & Macarena Siri & Nicky W. Tam & Ziliang Zhao & Leonel Malacrida & Rumiana Dimova, 2023. "Biomolecular condensates modulate membrane lipid packing and hydration," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    7. Thomas Litschel & Charlotte F. Kelley & Xiaohang Cheng & Leon Babl & Naoko Mizuno & Lindsay B. Case & Petra Schwille, 2024. "Membrane-induced 2D phase separation of the focal adhesion protein talin," Nature Communications, Nature, vol. 15(1), pages 1-13, December.

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