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Dynamic membrane repair is essential not only for long-term maintenance of cellular integrity but also for recovery from acute cell injury. While compromised membrane repair contributes to various pathological states, including muscular dystrophy, heart failure and neurodegeneration, the associated molecular machinery is largely unknown. We have recently found MG53, a muscle-specific tri-partite motif family protein (TRIM72), is a component of the sarcolemmal membrane-repair machinery. Mice null for MG53 exhibit progressive myopathy, reduced exercise capability and defective membrane-repair capacity. MG53 interacts with phosphatidylserine to associate with intracellular vesicles that display trafficking to and fusion with sarcolemmal membranes. Injury of the sarcolemmal membrane leads to MG53 oligomerization in an oxidation-dependent manner that results in recruitment of MG53-containing vesicles to …