Come on mtDNA, light my fire

Lawrence, Grace M.E.P.; Holley, Caroline L.; Schroder, Kate

doi:10.1016/j.immuni.2022.07.011

Cited by 8 publications

(3 citation statements)

References 9 publications

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“…Both mtROS and mtDNA are active factors that induce NLRP3 inflammasome [39]. In particular, cytosolic, oxidized mtDNA can activate the inflammasome by binding to the inflammasome sensors AIM2 and NL RP3 [62].…”

Section: Discussionmentioning

confidence: 99%

Glycine-Alanine Dipeptide Repeat Protein from C9-ALS Interacts with Sulfide Quinone Oxidoreductase (SQOR) to Induce the Activity of the NLRP3 Inflammasome in HMC3 Microglia: Irisflorentin Reverses This Interaction

Fu,

Chen,

Hong

2023

Antioxidants

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Amyotrophic lateral sclerosis (ALS) is a fatal rare disease of progressive degeneration of motor neurons. The most common genetic mutation in ALS is the hexanucleotide repeat expansion (HRE) located in the first intron of the C9orf72 gene (C9-ALS). HRE can produce dipeptide repeat proteins (DPRs) such as poly glycine-alanine (GA) in a repeat-associated non-ATG (RAN) translation. GA-DPR has been shown to be toxic to motor neurons in various biological models. However, its effects on microglia involved in C9-ALS have not been reported. Here, we show that GA-DPR (GA50) activates the NLR family pyrin domain containing 3 (NLRP3) inflammasome in a human HMC3 microglia model. MCC950 (specific inhibitor of the NLRP3) treatment can abrogate this activity. Next, using yeast two-hybrid screening, we identified sulfide quinone oxidoreductase (SQOR) as a GA50 interacting protein. SQOR knockdown in HMC3 cells can significantly induce the activity of the NLRP3 inflammasome by upregulating the level of intracellular reactive oxygen species and the cytoplasmic escape of mitochondrial DNA. Furthermore, we obtained irisflorentin as an effective blocker of the interaction between SQOR and GA50, thus inhibiting NLRP3 inflammasome activity in GA50-expressing HMC3 cells. These results imply the association of GA-DPR, SQOR, and NLRP3 inflammasomes in microglia and establish a treatment strategy for C9-ALS with irisflorentin.

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Section: Discussionmentioning

confidence: 99%

Glycine-Alanine Dipeptide Repeat Protein from C9-ALS Interacts with Sulfide Quinone Oxidoreductase (SQOR) to Induce the Activity of the NLRP3 Inflammasome in HMC3 Microglia: Irisflorentin Reverses This Interaction

Fu,

Chen,

Hong

2023

Antioxidants

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“…Mitochondria regulates the innate immune system through the release of numerous pro-inflammatory signals, such as mitochondrial reactive oxygen species (mtROS), mitochondrial DNA (mtDNA) and Ca 2+ , which is vital for the inflammasomes and cGAS-STING pathways activation (Fig. 2) [99][100][101][102]. Exposure of newly synthesized mtDNA to ROS induces oxidized mtDNA (Ox-mtDNA) production [103].…”

Section: Ox-mtdna and Mtrosmentioning

confidence: 99%

cGAS-STING, inflammasomes and pyroptosis: an overview of crosstalk mechanism of activation and regulation

Liu,

Zhou,

Luan

et al. 2024

Cell Commun Signal

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Background Intracellular DNA-sensing pathway cGAS-STING, inflammasomes and pyroptosis act as critical natural immune signaling axes for microbial infection, chronic inflammation, cancer progression and organ degeneration, but the mechanism and regulation of the crosstalk network remain unclear. Main body of the abstract Cellular stress disrupts mitochondrial homeostasis, facilitates the opening of mitochondrial permeability transition pore and the leakage of mitochondrial DNA to cell membrane, triggers inflammatory responses by activating cGAS-STING signaling, and subsequently induces inflammasomes activation and the onset of pyroptosis. Meanwhile, the inflammasome-associated protein caspase-1, Gasdermin D, the CARD domain of ASC and the potassium channel are involved in regulating cGAS-STING pathway. Importantly, this crosstalk network has a cascade amplification effect that exacerbates the immuno-inflammatory response, worsening the pathological process of inflammatory and autoimmune diseases. Given the importance of this crosstalk network of cGAS-STING, inflammasomes and pyroptosis in the regulation of innate immunity, it is emerging as a new avenue to explore the mechanisms of multiple disease pathogenesis. Therefore, efforts to define strategies to selectively modulate cGAS-STING, inflammasomes and pyroptosis in different disease settings have been or are ongoing. In this review, we will describe how this mechanistic understanding is driving possible therapeutics targeting this crosstalk network, focusing on the interacting or regulatory proteins, pathways, and a regulatory mitochondrial hub between cGAS-STING, inflammasomes, and pyroptosis. Short conclusion This review aims to provide insight into the critical roles and regulatory mechanisms of the crosstalk network of cGAS-STING, inflammasomes and pyroptosis, and to highlight some promising directions for future research and intervention.

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“…However, the efficacy of Pt chemotherapy drugs alone is limited due to the cellular self-protection mechanism. Recent studies have demonstrated that mtDNA can activate the host immune response of tumor cells by coordinating intracellular signaling pathways, including STING, and simultaneously triggering cellular inflammatory responses, promoting the expression of the NOD-like receptor protein (NLRP3) inflammasome 32 , 33 . Therefore, we hypothesize that amplifying the chemo-immunotherapeutic capacity of Pt drugs through mitochondrial membrane remodeling could eventually improve their anti-tumor effect.…”

Section: Introductionmentioning

confidence: 99%

Novel Pt(IV) complex OAP2 induces STING activation and pyroptosis via mitochondrial membrane remodeling for synergistic chemo-immunotherapy

Fan,

Lin,

Zhang

et al. 2024

Acta Pharmaceutica Sinica B

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Come on mtDNA, light my fire

Cited by 8 publications

References 9 publications

Glycine-Alanine Dipeptide Repeat Protein from C9-ALS Interacts with Sulfide Quinone Oxidoreductase (SQOR) to Induce the Activity of the NLRP3 Inflammasome in HMC3 Microglia: Irisflorentin Reverses This Interaction

Glycine-Alanine Dipeptide Repeat Protein from C9-ALS Interacts with Sulfide Quinone Oxidoreductase (SQOR) to Induce the Activity of the NLRP3 Inflammasome in HMC3 Microglia: Irisflorentin Reverses This Interaction

cGAS-STING, inflammasomes and pyroptosis: an overview of crosstalk mechanism of activation and regulation

Novel Pt(IV) complex OAP2 induces STING activation and pyroptosis via mitochondrial membrane remodeling for synergistic chemo-immunotherapy

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