Repair of acute damage to the plasma membrane is an important aspect of normal cellular physiology and disruption of this process can result in pathophysiology in a number of human diseases including muscular dystrophy. We recently discovered that MG53, a muscle-specific TRIM-family protein, is an essential component of the membrane repair machinery. While our published data define the sensor function for MG53 in cell membrane repair, the molecular mechanisms underlying the nucleation process remain to be defined. Since MG53 can discriminate between intact and injured membrane, a membrane-delimited signal would likely be involved in tethering of MG53 to the injured site. In pilot studie, we found that PTRF is an obligatory factor for MG53-mediated nucleation of the membrane repair response, for cells lacking endogenous expression of PTRF show defective membrane resealing. While RNAi- silencing of PTRF leads to defective membrane repair in muscle fibers, overexpression of PTRF can rescue this defect in dysferlin-/- muscle but not in mg53-/- muscle, suggesting that the functional role of PTRF in membrane repair likely requires the presence of MG53. While many studies have explored the function of PTRF in regulating caveolae structure of the plasma membrane, our data present a new biological function for PTRF as an anchoring molecule for MG53 for initiation of the cell membrane repair response. Since mutations in PTRF have been identified in human disorders with lipodystrophy and muscular dystrophy, conditions that often involve compromised membrane integrity or resealing capacity, targeting the functional interaction between MG53 and PTRF, or restoration of the disrupted MG53-PTRF interaction in the diseased states, may represent an attractive avenue for treatment or prevention of degenerative diseases involving compromised membrane repair. The long-term goal of this project is to understand the cellular and molecular mechanism for membrane repair in muscle physiology and diseases. Specifically, we will focus on testing the hypothesis that "PTRF acts as a docking protein for MG53-mediated cell membrane repair, and restoration of membrane integrity in muscular dystrophy can be achieved through enhancement of MG53/PTRF function at the interface of membrane injury". Our proposed studies will focus on defining the molecular mechanism underlying the functional interaction between MG53 and PTRF for initiation of the cell membrane repair response in skeletal muscle (Aim 1);and exploring the physiological role of MG53 and PTRF in muscle physiology and diseases and test if enhancement of PTRF-MG53 function can improve membrane integrity in muscular dystrophy (Aim 2). Through tailored-expression of MG53 and PTRF and the use of biochemical markers, live cell imaging, ex vivo and in vivo animal model studies, the designed experiments will provide key proof-of-principle data for targeting MG53/PTRF-mediated cell membrane repair in treatment of muscular dystrophy.
A major challenge in the field of regenerative medicine is developing novel therapeutic approaches to facilitate recovery of injury to skeletal muscle. This project originates from our recent discovery of MG53 as an essential component of the acute membrane repair machinery in muscle cells. Our research and development effort over the past three years have established several key findings that support the feasibility of our goal of targeting MG53-mediated membrane repair in muscle physiology and disease, in particular with the identification of an MG53-interacting protein as a key player for the assembly of the membrane repair patch. The studies proposed here present a unique opportunity to advance the field of regenerative medicine and to make significant progress in translating MG53 and PTRF into therapeutic agents for treatment or prevention of muscular dystrophy.
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|Tan, Tao; Ko, Young-Gyu; Ma, Jianjie (2016) Dual function of MG53 in membrane repair and insulin signaling. BMB Rep 49:414-23|
|Xu, Li; Park, Ki Ho; Zhao, Lixia et al. (2016) CRISPR-mediated Genome Editing Restores Dystrophin Expression and Function in mdx Mice. Mol Ther 24:564-9|
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|Ahn, Mi Kyoung; Lee, Keon Jin; Cai, Chuanxi et al. (2016) Mitsugumin 53 regulates extracellular Ca(2+) entry and intracellular Ca(2+) release via Orai1 and RyR1 in skeletal muscle. Sci Rep 6:36909|
|Huang, Jiaqing; Gumpper, Kristyn; Chi, Yuejie et al. (2015) Fast two-dimensional super-resolution image reconstruction algorithm for ultra-high emitter density. Opt Lett 40:2989-92|
|Cai, Chuanxi; Lin, Peihui; Zhu, Hua et al. (2015) Zinc Binding to MG53 Protein Facilitates Repair of Injury to Cell Membranes. J Biol Chem 290:13830-9|
|Li, Haichang; Duann, Pu; Lin, Pei-Hui et al. (2015) Modulation of wound healing and scar formation by MG53 protein-mediated cell membrane repair. J Biol Chem 290:24592-603|
|Duann, Pu; Li, Haichang; Lin, Peihui et al. (2015) MG53-mediated cell membrane repair protects against acute kidney injury. Sci Transl Med 7:279ra36|
|Lin, Pei-Hui; Duann, Pu; Komazaki, Shinji et al. (2015) Lysosomal two-pore channel subtype 2 (TPC2) regulates skeletal muscle autophagic signaling. J Biol Chem 290:3377-89|
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