Protein Therapeutics for Restoration of Membrane Integrity
We recently discovered that Mitsuguimin 53 (MG53), a muscle-specific TRIM-family protein (TRIM72), is an essential component of the acute membrane repair machinery. MG53 acts as a sensor of oxidation to nucleate recruitment of intracellular vesicles to the injury site for membrane patch formation. We found that MG53 can interact with dysferlin to facilitate its membrane repair function, and the membrane trafficking function of MG53 can be modulated through a functional interaction with Cav3. Our data indicate that a molecular complex formed by MG53, dysferlin and Cav3 is essential for repair of muscle membrane damage, and also provide a therapeutic target for treatment of muscular and cardiovascular diseases that are linked to compromised membrane repair. Because MG53 is a soluble, circulating protein, it could hypothetically be administered systemically. We are evaluating the pharmokinetics and antigenicity of MG53 as a precursor to clinical trials, and studying the effects of MG53 administration in dysferlin-deficient cells and animal models.