Autoantibodies targeting TRIM72 compromise membrane repair and contribute to inflammatory myopathy

McElhanon, Kevin E.; Young, Murray; Hampton, J.; Paleo, Brian J.; Kwiatkowski, Thomas A.; Beck, Eric X; Capati, Ana; Jablonski, Kyle; Gurney, Travis O.; Perez, Miguel A. Lopez; Aggarwal, Rohit; Oddis, Chester V.; Weisleder, Noah

doi:10.1172/jci131721

Cited by 10 publications

(7 citation statements)

References 68 publications

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“…MG53 is a muscle-enriched TRIM protein initially identified as a prominent component of plasma membrane repair machinery. 22,26,42,43 However, the actions of MG53 are not confined to skeletal muscle, and MG53 can be released into the circulation as a myokine. 32 We have previously shown MG53 can control inflammation during tissue damage in remote organs.…”

Section: Discussionmentioning

confidence: 99%

The cell membrane repair protein MG53 modulates transcription factor NF-κB signaling to control kidney fibrosis

Duann

et al. 2022

Kidney International

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Section: Discussionmentioning

confidence: 99%

The cell membrane repair protein MG53 modulates transcription factor NF-κB signaling to control kidney fibrosis

Duann

et al. 2022

Kidney International

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“…Autoantibodies targeting critical repair proteins (including anti-TRIM72/MG53 antibodies) may compromise membrane barrier function and promote progression of pathophysiology (establishing a feedback loop where decreased sarcolemma integrity promotes decreased resealing and increased antigen presentation). Thus, the autoimmune response triggered is primed to initiate a significant inflammatory response at the site of injury 84 . This was modelled in synaptotagim VII-deficient mouse models, which are defective in lysosomal exocytosis and resealing after wounding.…”

Section: Skeletal Muscle Injuriesmentioning

confidence: 99%

“…The pathology is not muscle-specific, being associated with severe neurodegeneration. Some MDs are idiopathic inflammatory myopathies (myositis), characterised by a chronic state of inflammation driven by abnormal membrane permeability that eventually results in the degeneration of muscle structure and function 84,85 . Once again, abnormal membrane resealing is believed to be an early event in these pathologies, resulting in increased exposure to intramuscular antigens, which activates the immune system.…”

Section: Pathological Conditionsmentioning

confidence: 99%

Plasma membrane integrity in health and disease: significance and therapeutic potential

2021

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Maintenance of plasma membrane integrity is essential for normal cell viability and function. Thus, robust membrane repair mechanisms have evolved to counteract the eminent threat of a torn plasma membrane. Different repair mechanisms and the bio-physical parameters required for efficient repair are now emerging from different research groups. However, less is known about when these mechanisms come into play. This review focuses on the existence of membrane disruptions and repair mechanisms in both physiological and pathological conditions, and across multiple cell types, albeit to different degrees. Fundamentally, irrespective of the source of membrane disruption, aberrant calcium influx is the common stimulus that activates the membrane repair response. Inadequate repair responses can tip the balance between physiology and pathology, highlighting the significance of plasma membrane integrity. For example, an over-activated repair response can promote cancer invasion, while the inability to efficiently repair membrane can drive neurodegeneration and muscular dystrophies. The interdisciplinary view explored here emphasises the widespread potential of targeting plasma membrane repair mechanisms for therapeutic purposes.

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“…Recently, researches point out that the TRIM72 overexpression could facilitate mitophagy in atrophic skeletal muscle of chronic kidney disease model and C2C12 cells [15]. Autoantibodies aiming at TRIM72 exacerbate idiopathic inflammatory myopathy [16]. Regulation of TRIM72 might mitigate inflammation through NF-κB pathway both in vivo and vitro [17][18][19][20].…”

Section: Introductionmentioning

confidence: 99%

TRIM72 Alleviates Muscle Inflammation in mdx Mice via Promoting Mitophagy-Mediated NLRP3 Inflammasome Inactivation

et al. 2023

Oxidative Medicine and Cellular Longevity

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Chronic muscle inflammation exacerbates the pathogenesis of Duchenne muscular dystrophy (DMD), which is characterized by progressive muscle degeneration and weakness. NLRP3 (nucleotide-binding domain and leucine-rich repeat pyrin domain containing 3) inflammasome plays a key role in the inflammatory process, and its abnormal activation leads to a variety of inflammatory or immune diseases. TRIM72 (MG53) is a protective myokine for tissue repair and regeneration. However, little is known about the potential impact of TRIM72 in the crosstalk between mitophagy and inflammatory process of DMD. Here, 10-week-old male mdx mice were injected intramuscularly with adeno-associated virus (AAV-TRIM72) to overexpress TRIM72 protein for 6 weeks. Then, skeletal muscle samples were collected, and relevant parameters were measured by histopathological analysis and molecular biology techniques. C2C12 cell line was transfected with lentivirus (LV-TRIM72) to overexpress or siRNA (si-TRIM72) to suppress the TRIM72 expression for the following experiment. Our data firstly showed that the TRIM72 expression was decreased in skeletal muscles of mdx mice. Then, we observed the increased NLRP3 inflammasome and impaired mitophagy in mdx mice compared with wild type mice. In mdx mice, administration of AAV-TRIM72 alleviated the accumulation of NLRP3 inflammasome and the consequent IL-18 and IL1β maturation by inducing autophagy, while this protective effect was reversed by chloroquine. Mitochondrial reactive oxygen species (mtROS), as a recognized activator for NLRP3 inflammasome, was attenuated by TRIM72 through the induction of mitophagy in C2C12 cells. Additionally, we proposed that the TRIM72 overexpression might promote mitophagy through both the early stage by PI3K-AKT pathway and the late stage by autolysosome fusion. In conclusion, the current study suggests that TRIM72 prevents DMD inflammation via decreasing NLRP3 inflammasomes and enhancing mitophagy. Collectively, our study provides insight into TRIM72 as a promising target for therapeutic intervention for DMD.

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Autoantibodies targeting TRIM72 compromise membrane repair and contribute to inflammatory myopathy

Cited by 10 publications

References 68 publications

The cell membrane repair protein MG53 modulates transcription factor NF-κB signaling to control kidney fibrosis

The cell membrane repair protein MG53 modulates transcription factor NF-κB signaling to control kidney fibrosis

Plasma membrane integrity in health and disease: significance and therapeutic potential

TRIM72 Alleviates Muscle Inflammation in mdx Mice via Promoting Mitophagy-Mediated NLRP3 Inflammasome Inactivation

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