Abstract
Biomolecular condensation driven by liquid–liquid phase separation (LLPS) is key to assembly of membraneless organelles in numerous crucial pathways. It is largely unknown how cellular structures or components spatiotemporally regulate LLPS and condensate formation. Here we reveal that cytoskeletal dynamics can control the condensation of p62 bodies comprising the autophagic adaptor p62/SQSTM1 and poly-ubiquitinated cargos. Branched actin networks are associated with p62 bodies and are required for their condensation. Myosin 1D, a branched actin-associated motor protein, drives coalescence of small nanoscale p62 bodies into large micron-scale condensates along the branched actin network. Impairment of actin cytoskeletal networks compromises the condensation of p62 bodies and retards substrate degradation by autophagy in both cellular models and Myosin 1D knockout mice. Coupling of LLPS scaffold to cytoskeleton systems may represent a general mechanism by which cells exert spatiotemporal control over phase condensation processes.
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Acknowledgements
We are grateful to members of the groups of L.Y., P.L., S.H. and N.M. for helpful discussions. We thank the group of Dr. Hongwei Wang (Tsinghua University, Beijing) for assistance with actin polymerization. We thank the State Key Laboratory of Membrane Biology for confocal microscopy imaging and facility support. We would also like to acknowledge the Center of Biomedical Analysis, Tsinghua University, for assistance with Andor high-speed confocal Dragonfly microscopy and Imaris analysis. This work was supported by the Ministry of Science and Technology of China (2017YFA0506300 to N.M.; 2019YFA0508403 to P.L.), and the National Natural Science Foundation of China (31771536 and 31860316).
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N.M. conceived the study; N.M. and P.L. wrote the manuscript and supervised the project; X. Feng, W.D., M.D. and X.X. performed most of the experiments. M.M., X.L., D.S., Q.X., Y.A. and Q.C. contributed to parts of the experiments. Y.L. helped with the electron microscopy. L.Y. provided insightful suggestions. W.Z. and W.W. helped with Imaris analysis. Y.Z., J.S., S.H. and X. Fu helped with actin polymerization. All the authors discussed and commented on the manuscript.
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Feng, X., Du, W., Ding, M. et al. Myosin 1D and the branched actin network control the condensation of p62 bodies. Cell Res 32, 659–669 (2022). https://doi.org/10.1038/s41422-022-00662-6
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DOI: https://doi.org/10.1038/s41422-022-00662-6
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