MG53 nucleates assembly of cell membrane repair machinery

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 Ca 2+ facilitates vesicle fusion to reseal the membrane. Our data indicate that intracellular vesicle translocation and Ca 2+ -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.To maintain cellular homeostasis, eukaryotic cells must conserve the integrity of their plasma membrane through active recycling and repair in response to various sources of damage 1 . Defects in the intrinsic membrane repair response have been linked to numerous disease states, including muscular dystrophy, heart failure and neurodegeneration [2][3][4][5] . Repair of plasma membrane damage requires recruitment of intracellular vesicles to injury sites 6,7 . One protein that has been linked to membrane repair in skeletal muscle is dysferlin [8][9][10] , which is thought to act as a fusogen that participates in restoration of sarcolemmal membrane integrity following muscle injury. Evidence for this role of dysferlin comes, in part, from studies showing that ablation of dysferlin in mice results in muscular dystrophy 8 .Repair of damage to the plasma membrane is an active and dynamic process that requires several steps, including participation of molecular sensor(s) that can detect acute injury to 6 Correspondence should be addressed to J.M. or H.T. (maj2@umdnj.edu; takeshim@pharm.kyoto-u.ac.jp).Note: Supplementary Information is available on the Nature Cell Biology website. COMPETING FINANCIAL INTERESTSThe authors declare no competing financial interests. NIH Public Access Author ManuscriptNat Cell Biol. Author manuscript; available in PMC 2010 November 23. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript the plasma membrane, nucleation of intracellular vesicles at the injury site and vesicle fusion to enable membrane patch formation. It is well demonstrated that entry of extracellular Ca 2+ is involved in the fusion of intracellular vesicles to reseal the injured plasma membrane 6,11,12 , whereas the molecular machinery involved in sensing the damaged membrane signal and the nucleation process for repair-patch formation have not been fully resolved.We have previously established an immunopr...

MG53 Regulates Membrane Budding and Exocytosis in Muscle Cells

“…Our previous studies showed that MG53 can function in the repair of sarcolemmal membrane following acute cell injury (22). Those finding are consistent with our observation here that MG53 participates in vesicle trafficking in the course of normal cellular physiology.…”

“…1C, left panels). This result is consistent with our electron microscopic localization of MG53 in skeletal muscle fibers (22) and suggests that MG53 may participate in membrane trafficking events in muscle cells.…”

“…Live cell fluorescence imaging identified dynamic trafficking of intracellular vesicles and active exocytotic fusion and vesicle budding at the cell surface membrane in cells overexpressing GFP-MG53 (22). Close examination revealed the occurrence of vesicle fusion events at the surface membrane (Fig.…”

“…Further studies identified mitsugumin 29, a synaptophysin-related protein that is essential for biogen-esis of triad membrane structures and Ca 2ϩ signaling in skeletal muscle (20,21). Screening of this immunoproteomics library led to the recent identification of MG53, a muscle-specific TRIM family protein (22). Domain homology analysis revealed that MG53 contains the prototypical RBCC motifs plus a SPRY domain at the carboxyl terminus.…”

“…Domain homology analysis revealed that MG53 contains the prototypical RBCC motifs plus a SPRY domain at the carboxyl terminus. Genetic knock-out and functional studies reveal that MG53 nucleates the assembly of the sarcolemmal membrane repair machinery to restore cellular integrity following acute damage to the muscle fiber (22).…”