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Liquid-liquid phase separation in biology: mechanisms, physiological functions and human diseases

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Abstract

Cells are compartmentalized by numerous membrane-enclosed organelles and membraneless compartments to ensure that a wide variety of cellular activities occur in a spatially and temporally controlled manner. The molecular mechanisms underlying the dynamics of membrane-bound organelles, such as their fusion and fission, vesicle-mediated trafficking and membrane contactmediated inter-organelle interactions, have been extensively characterized. However, the molecular details of the assembly and functions of membraneless compartments remain elusive. Mounting evidence has emerged recently that a large number of membraneless compartments, collectively called biomacromolecular condensates, are assembled via liquid-liquid phase separation (LLPS). Phase-separated condensates participate in various biological activities, including higher-order chromatin organization, gene expression, triage of misfolded or unwanted proteins for autophagic degradation, assembly of signaling clusters and actin- and microtubule-based cytoskeletal networks, asymmetric segregations of cell fate determinants and formation of pre- and post-synaptic density signaling assemblies. Biomacromolecular condensates can transition into different material states such as gel-like structures and solid aggregates. The material properties of condensates are crucial for fulfilment of their distinct functions, such as biochemical reaction centers, signaling hubs and supporting architectures. Cells have evolved multiple mechanisms to ensure that biomacromolecular condensates are assembled and disassembled in a tightly controlled manner. Aberrant phase separation and transition are causatively associated with a variety of human diseases such as neurodegenerative diseases and cancers. This review summarizes recent major progress in elucidating the roles of LLPS in various biological pathways and diseases.

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Acknowledgements

We are grateful to Dr. Isabel Hanson for editing work. Work in Hong Zhang’s laboratory was supported by grants from the Beijing Municipal Science and Technology Committee (Z181100001318003), the National Natural Science Foundation of China (31421002, 31561143001, 31630048, and 31790403), the Ministry of Science and Technology of China (2017YFA0503401), the Strategic Priority Research Program of the Chinese Academy of Sciences (CAS) (XDB19000000) and the Key Research Program of Frontier Sciences, CAS (QYZDY-SSW-SMC006). Work in Xiong Ji’s laboratory was supported by funds from the Ministry of Science and Technology of China and the National Natural Science Foundation of China (2017YFA0506600 and 31871309). Work in Pilong Li’s laboratory was supported by funds from the Ministry of Science and Technology of China and the National Natural Science Foundation of China (2019YFA0508403 and 31871443). Work in Cong Liu’s laboratory was supported by grants from the Ministry of Science and Technology of China (2016YFA0501902), the National Natural Science Foundation of China (91853113 and 31872716), the Science and Technology Commission of Shanghai Municipality (18JC1420500), the Shanghai Municipal Science and Technology Major Project (2019SHZDZX02). Work in Jizhong Lou’s laboratory was supported by grants from the Ministry of Science and Technology of China (2019YFA0707000), the National Natural Science Foundation of China (11672317). Work in Wenyu Wen’s laboratory was supported by grants from the Ministry of Science and Technology of China (2019YFA0508401), the National Natural Science Foundation of China (31871394 and 31670730), the Shanghai Municipal Science and Technology Major Project (2018SHZDZX01) and ZJLab. Work in Xueliang Zhu’s laboratory was supported by grants from the National Natural Science Foundation of China (31420103916 and 31991192) and CAS (XDB19020102). Research in Mingjie Zhang’s laboratory was supported by grants from RGC of Hong Kong (AoE-M09-12 and C6004-17G) and National Key R&D Program of China (2016YFA0501903 and 2019YFA0508402).

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Authors and Affiliations

  1. National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China

    Hong Zhang & Zheng Wang

  2. College of Life Sciences, University of Chinese Academy of Sciences, Beijing, 100049, China

    Hong Zhang & Jizhong Lou

  3. Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, School of Life Sciences, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, 100871, China

    Xiong Ji

  4. Beijing Advanced Innovation Center for Structural Biology, Beijing Frontier Research Center for Biological Structure, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, 100084, China

    Pilong Li

  5. Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, 201210, China

    Cong Liu

  6. Key Laboratory of RNA Biology, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China

    Jizhong Lou

  7. State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Biomedical Sciences, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China

    Wenyu Wen

  8. State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, 200031, China

    Yue Xiao & Xueliang Zhu

  9. Division of Life Science, State Key Laboratory of Molecular Neuroscience, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China

    Mingjie Zhang

Authors
  1. Hong Zhang
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  2. Xiong Ji
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  3. Pilong Li
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  4. Cong Liu
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  7. Wenyu Wen
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  8. Yue Xiao
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  9. Mingjie Zhang
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  10. Xueliang Zhu
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Corresponding authors

Correspondence to Hong Zhang, Xiong Ji, Pilong Li, Cong Liu, Jizhong Lou, Wenyu Wen, Mingjie Zhang or Xueliang Zhu.

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Zhang, H., Ji, X., Li, P. et al. Liquid-liquid phase separation in biology: mechanisms, physiological functions and human diseases. Sci. China Life Sci. 63, 953–985 (2020). https://doi.org/10.1007/s11427-020-1702-x

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  • DOI: https://doi.org/10.1007/s11427-020-1702-x

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