MG53, A Tissue Repair Protein with Broad Applications in Regenerative Medicine

Li, Zhong-Guang; Wang, Liyang; Yue, Huimin; Whitson, Bryan A.; Haggard, Erin; Xu, Xuehong; Ma, Jianjie

doi:10.3390/cells10010122

Cited by 31 publications

(35 citation statements)

References 79 publications

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“…MG53, as a muscle-derived protein that circulates in the bloodstream, is known to facilitate repair of injury to multiple vital organs [81,82]. The tumor suppressor function of MG53 has just started to be appreciated.…”

Section: Discussionmentioning

confidence: 99%

MG53 suppresses tumor progression and stress granule formation by modulating G3BP2 activity in non-small cell lung cancer

Lin

Gupta

et al. 2021

Mol Cancer

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Background Cancer cells develop resistance to chemotherapeutic intervention by excessive formation of stress granules (SGs), which are modulated by an oncogenic protein G3BP2. Selective control of G3BP2/SG signaling is a potential means to treat non-small cell lung cancer (NSCLC). Methods Co-immunoprecipitation was conducted to identify the interaction of MG53 and G3BP2. Immunohistochemistry and live cell imaging were performed to visualize the subcellular expression or co-localization. We used shRNA to knock-down the expression MG53 or G3BP2 to test the cell migration and colony formation. The expression level of MG53 and G3BP2 in human NSCLC tissues was tested by western blot analysis. The ATO-induced oxidative stress model was used to examine the effect of rhMG53 on SG formation. Moue NSCLC allograft experiments were performed on wild type and transgenic mice with either knockout of MG53, or overexpression of MG53. Human NSCLC xenograft model in mice was used to evaluate the effect of MG53 overexpression on tumorigenesis. Results We show that MG53, a member of the TRIM protein family (TRIM72), modulates G3BP2 activity to control lung cancer progression. Loss of MG53 results in the progressive development of lung cancer in mg53-/- mice. Transgenic mice with sustained elevation of MG53 in the bloodstream demonstrate reduced tumor growth following allograft transplantation of mouse NSCLC cells. Biochemical assay reveals physical interaction between G3BP2 and MG53 through the TRIM domain of MG53. Knockdown of MG53 enhances proliferation and migration of NSCLC cells, whereas reduced tumorigenicity is seen in NSCLC cells with knockdown of G3BP2 expression. The recombinant human MG53 (rhMG53) protein can enter the NSCLC cells to induce nuclear translation of G3BP2 and block arsenic trioxide-induced SG formation. The anti-proliferative effect of rhMG53 on NSCLC cells was abolished with knockout of G3BP2. rhMG53 can enhance sensitivity of NSCLC cells to undergo cell death upon treatment with cisplatin. Tailored induction of MG53 expression in NSCLC cells suppresses lung cancer growth via reduced SG formation in a xenograft model. Conclusion Overall, these findings support the notion that MG53 functions as a tumor suppressor by targeting G3BP2/SG activity in NSCLCs.

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Section: Discussionmentioning

confidence: 99%

MG53 suppresses tumor progression and stress granule formation by modulating G3BP2 activity in non-small cell lung cancer

Lin

Gupta

et al. 2021

Mol Cancer

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“…MG53 protein can be released from skeletal muscle as a myokine [44]. In mdx mice, a model of Duchenne muscular dystrophy, we previously demonstrated that increased serum MG53 level correlated with an increased serum CK level [29], indicating that elevated serum MG53 level serves as a biomarker for muscle membrane damage.…”

Section: Mg53 Is Implicated In the Membrane Fragility Of G93a Diaphragm Fast-and Slow-type Musclesmentioning

confidence: 94%

MG53 Preserves Neuromuscular Junction Integrity and Alleviates ALS Disease Progression

et al. 2021

Antioxidants

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Respiratory failure from progressive respiratory muscle weakness is the most common cause of death in amyotrophic lateral sclerosis (ALS). Defects in neuromuscular junctions (NMJs) and progressive NMJ loss occur at early stages, thus stabilizing and preserving NMJs represents a potential therapeutic strategy to slow ALS disease progression. Here we demonstrate that NMJ damage is repaired by MG53, an intrinsic muscle protein involved in plasma membrane repair. Compromised diaphragm muscle membrane repair and NMJ integrity are early pathological events in ALS. Diaphragm muscles from ALS mouse models show increased susceptibility to injury and intracellular MG53 aggregation, which is also a hallmark of human muscle samples from ALS patients. We show that systemic administration of recombinant human MG53 protein in ALS mice protects against injury to diaphragm muscle, preserves NMJ integrity, and slows ALS disease progression. As MG53 is present in circulation in rodents and humans under physiological conditions, our findings provide proof-of-concept data supporting MG53 as a potentially safe and effective therapy to mitigate ALS progression.

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“…At the membrane, TRIM72 protein binds to phosphatidyl serine to mediate the recruitment of vesicles at the injured site [104]. Interestingly, TRIM72 can be secreted and circulate throughout the entire body to reach all tissues and organs, allowing the recombinant TRIM72 protein to have therapeutic benefit in treatment of injuries to multiple tissues, such as the heart, kidney, lung, brain, liver, skin, skeletal muscle, and cornea [105]. Ablation of the TRIM72 gene leads to increased susceptibility to ischemia-reperfusion and overventilation-induced ALI in mice [97].…”

Section: Trim65mentioning

confidence: 99%

The Emerging Roles of Tripartite Motif Proteins (TRIMs) in Acute Lung Injury

Huang

Xiao

Zhang

et al. 2021

Journal of Immunology Research

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Acute lung injury (ALI) is an inflammatory disorder of the lung that causes high mortality and lacks any pharmacological intervention. Ubiquitination plays a critical role in the pathogenesis of ALI as it regulates the alveolocapillary barrier and the inflammatory response. Tripartite motif (TRIM) proteins are one of the subfamilies of the RING-type E3 ubiquitin ligases, which contains more than 80 distinct members in humans involved in a broad range of biological processes including antivirus innate immunity, development, and tumorigenesis. Recently, some studies have shown that several members of TRIM family proteins play important regulatory roles in inflammation and ALI. Herein, we integrate emerging evidence regarding the roles of TRIMs in ALI. Articles were selected from the searches of PubMed database that had the terms “acute lung injury,” “ubiquitin ligases,” “tripartite motif protein,” “inflammation,” and “ubiquitination” using both MeSH terms and keywords. Better understanding of these mechanisms may ultimately lead to novel therapeutic approaches by targeting TRIMs for ALI treatment.

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MG53, A Tissue Repair Protein with Broad Applications in Regenerative Medicine

Cited by 31 publications

References 79 publications

MG53 suppresses tumor progression and stress granule formation by modulating G3BP2 activity in non-small cell lung cancer

MG53 suppresses tumor progression and stress granule formation by modulating G3BP2 activity in non-small cell lung cancer

MG53 Preserves Neuromuscular Junction Integrity and Alleviates ALS Disease Progression

The Emerging Roles of Tripartite Motif Proteins (TRIMs) in Acute Lung Injury

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