Pnpt1 mediates NLRP3 inflammasome activation by MAVS and metabolic reprogramming in macrophages

Hsu, Chia George; Li, Wenjia; Sowden, Mark P.; Chávez, Camila Lage; Berk, Bradford C.

doi:10.1038/s41423-022-00962-2

Cited by 15 publications

(9 citation statements)

References 56 publications

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“…dsRNA is a known pathogen-associated molecular pattern that can trigger the assembly of MDA5 ATP-sensitive laments, that in turn activate the mitochondrial antiviral-signalling protein via CARD domain-mediated interactions [38]. Additionally, macrophage cell models have shown that Pnpt1 de ciency-mediated MAVS-activation results in NLRP3 in ammasome activation and mitochondrial reprograming, which in turn results in impaired mitochondrial function and decreased levels of cellular ATP [39,40]. Genetic defects that cause impaired nucleotide metabolism have been reported and are well established aetiologies of other IWMDs such as mutations in ADAR1, TREX1, SAMHD1, IFIH1 (which encodes MDA5), and RNASEH2B [41][42][43][44][45], resulting in a common pathway of genes involved in nucleotide metabolism that can trigger leukodystrophy-causing in ammation.…”

Section: Discussionmentioning

confidence: 99%

Biallelic mutations in SUPV3L1 cause an inherited neurodevelopmental disorder with variable leukodystrophy due to aberrant mitochondrial double stranded RNA processing

Green,

Hamilton,

Elpidorou

et al. 2024

Preprint

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We describe eighteen individuals from twelve families with an autosomal recessive neurodevelopmental disorder and variable leukodystrophy harbouring biallelic variants in SUPV3L1. SUPV3L1 encodes the RNA helicase SUV3 (also known as SUPV3L1), with previous studies demonstrating a role for the protein as part of the mitochondrial degradosome. Patient mutations result in an accumulation of mitochondrial double stranded RNAs in human cells. An assessment of supv3l1 knock-out zebrafish confirmed the role of supv3l1 in neurodevelopment, with gross defects identified in mitochondrial biogenesis and microglial function. Zebrafish displayed a significant activation of the type 1 interferon pathway, which was supported by qPCR of blood RNA from four patients with biallelic SUV3 mutations. Altogether, we describe a clinico-radiological spectrum associated with biallelic SUPV3L1 mutations, demonstrating that loss of SUV3 function results in altered mitochondrial biogenesis, increased mitochondrial double stranded RNA, dysplastic microglia and activation of the type 1 interferon innate immune pathway.

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Section: Discussionmentioning

confidence: 99%

Biallelic mutations in SUPV3L1 cause an inherited neurodevelopmental disorder with variable leukodystrophy due to aberrant mitochondrial double stranded RNA processing

Green,

Hamilton,

Elpidorou

et al. 2024

Preprint

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“…Nathan et al [ 45 ] reported different changes in meningeal and lymph node immune cell profiles between male and female mice. Inflammation is a process influenced by metabolism [ 46 , 47 ], and we therefore speculated that the different functions of Tregs may be attributed to the metabolic mode. Tregs used to be considered to regulate energy metabolism through oxidative phosphorylation of glucose and fatty acids.…”

Section: Discussionmentioning

confidence: 99%

Glucose competition between endothelial cells in the blood-spinal cord barrier and infiltrating regulatory T cells is linked to sleep restriction-induced hyperalgesia

Huang,

Xu,

Liu

et al. 2024

BMC Med

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Background Sleep loss is a common public health problem that causes hyperalgesia, especially that after surgery, which reduces the quality of life seriously. Methods The 48-h sleep restriction (SR) mouse model was created using restriction chambers. In vivo imaging, transmission electron microscopy (TEM), immunofluorescence staining and Western blot were performed to detect the status of the blood-spinal cord barrier (BSCB). Paw withdrawal mechanical threshold (PWMT) was measured to track mouse pain behavior. The role of infiltrating regulatory T cells (Tregs) and endothelial cells (ECs) in mouse glycolysis and BSCB damage were analyzed using flow cytometry, Western blot, CCK-8 assay, colorimetric method and lactate administration. Results The 48-h SR made mice in sleep disruption status and caused an acute damage to the BSCB, resulting in hyperalgesia and neuroinflammation in the spinal cord. In SR mice, the levels of glycolysis and glycolysis enzymes of ECs in the BSCB were found significantly decreased [CON group vs. SR group: CD31+Glut1+ cells: p < 0.001], which could cause dysfunction of ECs and this was confirmed in vitro. Increased numbers of infiltrating T cells [p < 0.0001] and Treg population [p < 0.05] were detected in the mouse spinal cord after 48-h SR. In the co-cultured system of ECs and Tregs in vitro, the competition of Tregs for glucose resulted in the glycolysis disorder of ECs [Glut1: p < 0.01, ENO1: p < 0.05, LDHα: p < 0.05; complete tubular structures formed: p < 0.0001; CCK8 assay: p < 0.001 on 24h, p < 0.0001 on 48h; glycolysis level: p < 0.0001]. An administration of sodium lactate partially rescued the function of ECs and relieved SR-induced hyperalgesia. Furthermore, the mTOR signaling pathway was excessively activated in ECs after SR in vivo and those under the inhibition of glycolysis or co-cultured with Tregs in vitro. Conclusions Affected by glycolysis disorders of ECs due to glucose competition with infiltrating Tregs through regulating the mTOR signaling pathway, hyperalgesia induced by 48-h SR is attributed to neuroinflammation and damages to the barriers, which can be relieved by lactate supplementation.

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“…Despite the necessity of the inflammasome activation in protecting against infections, the system results in unnecessary inflammatory diseases by inflammasome overactivation. [27][28][29] ZBP1 senses IAV through its Zα domain, allowing for interactions between RIPK3 and other related proteins, covering caspase-8/-6, RIPK1, etc., thus forming the ZBP1-PANoptosome complex and executing PANoptosis. Moreover, the ZBP1-PANoptosome enables to recruit the NLRP3 inflammasome as an essential element, resulting in activated inflammasome and IL-1β/-18 generation.…”

Section: Zbp1-panoptosomementioning

confidence: 99%

“…GSDMD is a gasdermin family sharing the pore‐forming domains. Despite the necessity of the inflammasome activation in protecting against infections, the system results in unnecessary inflammatory diseases by inflammasome overactivation 27–29 …”

Section: Components and Modulation Of The Panoptosome Complexesmentioning

confidence: 99%

PANoptosis: Mechanisms, biology, and role in disease

Sun,

Yang,

Meng

et al. 2023

Immunological Reviews

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SummaryCell death can be executed through distinct subroutines. PANoptosis is a unique inflammatory cell death modality involving the interactions between pyroptosis, apoptosis, and necroptosis, which can be mediated by multifaceted PANoptosome complexes assembled via integrating components from other cell death modalities. There is growing interest in the process and function of PANoptosis. Accumulating evidence suggests that PANoptosis occurs under diverse stimuli, for example, viral or bacterial infection, cytokine storm, and cancer. Given the impact of PANoptosis across the disease spectrum, this review briefly describes the relationships between pyroptosis, apoptosis, and necroptosis, highlights the key molecules in PANoptosome formation and PANoptosis activation, and outlines the multifaceted roles of PANoptosis in diseases together with a potential for therapeutic targeting. We also discuss important concepts and pressing issues for future PANoptosis research. Improved understanding of PANoptosis and its mechanisms is crucial for identifying novel therapeutic targets and strategies.

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Pnpt1 mediates NLRP3 inflammasome activation by MAVS and metabolic reprogramming in macrophages

Cited by 15 publications

References 56 publications

Biallelic mutations in SUPV3L1 cause an inherited neurodevelopmental disorder with variable leukodystrophy due to aberrant mitochondrial double stranded RNA processing

Biallelic mutations in SUPV3L1 cause an inherited neurodevelopmental disorder with variable leukodystrophy due to aberrant mitochondrial double stranded RNA processing

Glucose competition between endothelial cells in the blood-spinal cord barrier and infiltrating regulatory T cells is linked to sleep restriction-induced hyperalgesia

PANoptosis: Mechanisms, biology, and role in disease

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