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MG53 nucleates assembly of cell membrane repair machinery

Nature Cell Biology volume 11, pages 56–64 (2009)Cite this article

Abstract

Dynamic membrane repair and remodelling is an elemental process that maintains cell integrity and mediates efficient cellular function. Here we report that MG53, a muscle-specific tripartite motif family protein (TRIM72), is a component of the sarcolemmal membrane-repair machinery. MG53 interacts with phosphatidylserine to associate with intracellular vesicles that traffic to and fuse with sarcolemmal membranes. Mice null for MG53 show progressive myopathy and reduced exercise capability, associated with defective membrane-repair capacity. Injury of the sarcolemmal membrane leads to entry of the extracellular oxidative environment and MG53 oligomerization, resulting in recruitment of MG53-containing vesicles to the injury site. After vesicle translocation, entry of extracellular Ca2+ facilitates vesicle fusion to reseal the membrane. Our data indicate that intracellular vesicle translocation and Ca2+-dependent membrane fusion are distinct steps involved in the repair of membrane damage and that MG53 may initiate the assembly of the membrane repair machinery in an oxidation-dependent manner.

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Figure 1: Mice null for MG53, a muscle specific TRIM family protein, show progressive muscle pathology.
Figure 2: Defective membrane repair capacity in mg53−/− muscle.
Figure 3: MG53 facilitates repair of acute membrane damage in muscle cells.
Figure 4: Oxidation-mediated MG53 oligomerization serves as a nucleation mechanism for acute membrane repair.
Figure 5: Repair patch formation by MG53 restores cell integrity following acute injury.
Figure 6: MG53 binds to phosphatidylserine (PS) to mediate Ca2+-independent vesicle translocation to the injury site.
Figure 7: Relative contribution of extracellular Ca2+ and oxidation to membrane repair in skeletal muscle.
Figure 8: A schematic representation of the proposed function of MG53 in muscle membrane repair.

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Acknowledgements

We thank Michael Reid, Jerome Parness, and Heping Cheng for helpful suggestions to this work. Yi Chu provided assistance in data processing and graphic conversions. We also thank the Cancer Institute of New Jersey Tissue Analytic Services Shared Resource and the UMDNJ-Cell Imaging Core facility, which is supported by NCRR from NIH, for providing assistance with imaging. This work was supported by grants from NIH (J.M.), Ministry of Education, Science, Sports and Culture of Japan (H.T.) and the American Heart Association (C.C., N.W., M.B.).

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Authors and Affiliations

  1. Department of Physiology and Biophysics, Robert Wood Johnson Medical School, 675 Hoes Lane, Piscataway, 08854, NJ, USA

    Chuanxi Cai, Noah Weisleder, Moonsun Hwang, Jae-Kyun Ko, Peihui Lin, Angela Thornton, Xiaoli Zhao, Zui Pan, Marco Brotto & Jianjie Ma

  2. Department of Medical Chemistry, Graduate School of Medicine, Tohoku University, Japan

    Haruko Masumiya, Miyuki Nishi & Hiroshi Takeshima

  3. Center Laboratory of Frontier Science, The Tokyo Metropolitan Institute of Medical Science, Japan

    Noriyuki Matsuda

  4. Department of Biological Chemistry, Kyoto University Graduate School of Pharmaceutical Sciences, Kyoto, 606-8501, Japan

    Miyuki Nishi & Hiroshi Takeshima

  5. Department of Anatomy, Saitama Medical School, Saitama, 350-0495, Japan

    Shinji Komazaki

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Cai, C., Masumiya, H., Weisleder, N. et al. MG53 nucleates assembly of cell membrane repair machinery. Nat Cell Biol 11, 56–64 (2009). https://doi.org/10.1038/ncb1812

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