{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nTRIM72—also known as mitsugumin 53 (MG53)—plays a pivotal role in the rapid repair of plasma membrane disruptions. Acting as an E3‐ubiquitin ligase, TRIM72 facilitates the recruitment and fusion of intracellular vesicles at sites of membrane injury in skeletal and cardiac muscle, with its activity critically dependent on zinc‐binding motifs and unique structural features revealed by cryo‐EM studies. In muscle fibers, TRIM72 not only coordinates with docking proteins such as PTRF (to bind exposed membrane cholesterol) but also engages with the cytoskeletal motor machinery to promote vesicle trafficking to injury sites, thereby protecting cells from mechanical and oxidative stress and attenuating tissue damage. These membrane repair functions are demonstrated in models of muscular dystrophy, ischemia/reperfusion injury, and even in non‐muscle contexts such as wound healing and cardioprotection."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "8"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its canonical role in membrane repair, TRIM72 influences key intracellular signaling pathways. In skeletal myogenesis, it mediates the ubiquitination and degradation of signaling molecules such as insulin receptor substrate 1 (IRS-1) and focal adhesion kinase (FAK), thereby modulating insulin-like growth factor and insulin signaling. In immune-competent cells like macrophages, TRIM72 expression helps regulate type I interferon production and NF-κB activation, conferring a modulatory influence on inflammatory responses. Moreover, in models of traumatic brain injury and other oxidative stress settings, TRIM72 enhances the survival of stem cells and protects against cellular apoptosis, underscoring its role as a broad stress-response mediator."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "9", "end_ref": "12"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nEmerging evidence also implicates TRIM72 in the regulation of disease processes beyond membrane repair. Structural and evolutionary studies suggest that variation in its expression may influence cardiac energy metabolism across species, while its E3 ligase function regulates proteins involved in chemoresistance in cancers such as uveal melanoma. In breast cancer, TRIM72 modulates the tumor microenvironment by affecting hypoxia-induced signaling cascades, and its regulatory actions extend to the alleviation of neuropathic pain and protection against anesthetic-induced neurotoxicity in neural stem cells through modulation of the Nrf2/HO-1 pathway. Collectively, these insights highlight TRIM72 not only as a central mediator of membrane integrity but also as a promising therapeutic target for a wide range of conditions—from metabolic and neurodegenerative disorders to cancer—where compromised membrane function or aberrant signaling contributes to pathology."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "13", "end_ref": "20"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Hua Zhu, Peihui Lin, Gejing De, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Dysferlin, annexin A1, and mitsugumin 53 are upregulated in muscular dystrophy and localize to longitudinal tubules of the T-system with stretch."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Neuropathol Exp Neurol (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1097/NEN.0b013e31821350b0"}], "href": "https://doi.org/10.1097/NEN.0b013e31821350b0"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21412170"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21412170"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Peihui Lin, Hua Zhu, Chuanxi Cai, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Zinc Binding to MG53 Protein Facilitates Repair of Injury to Cell Membranes."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M114.620690"}], "href": "https://doi.org/10.1074/jbc.M114.620690"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25869134"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25869134"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Haichang Li, Pu Duann, Pei-Hui Lin, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Inhibition of Macrophage Complement Receptor CRIg by TRIM72 Polarizes Innate Immunity of the Lung."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Respir Cell Mol Biol (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1165/rcmb.2017-0236OC"}], "href": "https://doi.org/10.1165/rcmb.2017-0236OC"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29268030"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29268030"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Fangxia Guan, Tuanjie Huang, Xinxin Wang, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Targeting TRIM Proteins: A Quest towards Drugging an Emerging Protein Class."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Chembiochem (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/cbic.202000787"}], "href": "https://doi.org/10.1002/cbic.202000787"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33482040"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33482040"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Yuanqing Feng, Hongzhan Xu, Jinghao Liu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Functional and Adaptive Significance of Promoter Mutations That Affect Divergent Myocardial Expressions of TRIM72 in Primates."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Biol Evol (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/molbev/msab083"}], "href": "https://doi.org/10.1093/molbev/msab083"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33744959"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33744959"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "Xun Li, Cong Yang, Ning Luo, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Ubiquitination and degradation of MGMT by TRIM72 increases the sensitivity of uveal melanoma cells to Dacarbazine treatment."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Biomark (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3233/CBM-210345"}], "href": "https://doi.org/10.3233/CBM-210345"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34958003"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34958003"}]}, {"type": "r", "ref": 16, "children": [{"type": "t", "text": "Zheng Wang, Haixia Li, Hongxia Wang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "TRIM72 exerts antitumor effects in breast cancer and modulates lactate production and MCT4 promoter activity by interacting with PPP3CA."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Anticancer Drugs (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1097/CAD.0000000000001304"}], "href": "https://doi.org/10.1097/CAD.0000000000001304"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "35324524"}], "href": "https://pubmed.ncbi.nlm.nih.gov/35324524"}]}, {"type": "r", "ref": 17, "children": [{"type": "t", "text": "Kun-Ming Cui, Zhen-Ping Hu, Ya-Li Wang "}, {"type": "b", "children": [{"type": "t", "text": "MG53 represses high glucose-induced inflammation and angiogenesis in human retinal endothelial cells by repressing the EGR1/STAT3 axis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Immunopharmacol Immunotoxicol (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1080/08923973.2022.2054426"}], "href": "https://doi.org/10.1080/08923973.2022.2054426"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "35438597"}], "href": "https://pubmed.ncbi.nlm.nih.gov/35438597"}]}, {"type": "r", "ref": 18, "children": [{"type": "t", "text": "Yange Niu, Gengjia Chen, Fengxiang Lv, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Cryo-EM structure of human MG53 homodimer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem J (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1042/BCJ20220385"}], "href": "https://doi.org/10.1042/BCJ20220385"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "36053137"}], "href": "https://pubmed.ncbi.nlm.nih.gov/36053137"}]}, {"type": "r", "ref": 19, "children": [{"type": "t", "text": "Minmin Cai, Xiang Gao, Shenghui Yu "}, {"type": "b", "children": [{"type": "t", "text": "Tripartite motif 72 inhibits apoptosis and mitochondrial dysfunction in neural stem cells induced by anesthetic sevoflurane by activating PI3K/AKT pathway."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Chin J Physiol (2023)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.4103/cjop.CJOP-D-22-00082"}], "href": "https://doi.org/10.4103/cjop.CJOP-D-22-00082"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "36814155"}], "href": "https://pubmed.ncbi.nlm.nih.gov/36814155"}]}, {"type": "r", "ref": 20, "children": [{"type": "t", "text": "Xuan-Zhi Zhu, Jing-Qiong Wang, Yao-Hua Wu "}, {"type": "b", "children": [{"type": "t", "text": "MG53 ameliorates nerve injury induced neuropathic pain through the regulation of Nrf2/HO-1 signaling in rats."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Behav Brain Res (2023)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbr.2023.114489"}], "href": "https://doi.org/10.1016/j.bbr.2023.114489"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "37169128"}], "href": "https://pubmed.ncbi.nlm.nih.gov/37169128"}]}]}]}