Mitochondrial quality control pathways sense mitochondrial protein import

Trends in Endocrinology and Metabolism, Journal Year: 2023, Volume and Issue: 35(4), P. 308 - 320

Published: Dec. 15, 2023

Language: Английский

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NLRX1 limits inflammatory neurodegeneration in the anterior visual pathway

Journal of Neuroinflammation, Journal Year: 2025, Volume and Issue: 22(1)

Published: Jan. 28, 2025

Chronic innate immune activation in the central nervous system (CNS) significantly contributes to neurodegeneration progressive multiple sclerosis (MS). Using experimental autoimmune encephalomyelitis (EAE) models, we discovered that NLRX1 protects neurons anterior visual pathway from inflammatory neurodegeneration. We quantified retinal ganglion cell (RGC) density and optic nerve axonal degeneration, gliosis, T-cell infiltration Nlrx1−/− wild-type (WT) EAE mice found increased RGC loss injury compared WT both active immunization spontaneous opticospinal (OSE) models. To minimize effects of on peripheral lymphocyte priming during EAE, performed adoptive transfer experiments, which activated myelin-specific T cells were transferred into lymphocyte-deficient Rag−/− or Nlrx1−/−Rag−/− mice. In this model, more severe microgliosis astrogliosis mice, suggesting a regulatory role cells. Transcriptome analysis primary astrocytes with LPS IFNγ demonstrated suppresses NF-κB regulates mitochondrial oxidative phosphorylation reactive astrocytes. The novel pharmacologic activators NX-13 LABP-66 decreased LPS-mediated gene expression cytokines chemokines mixed glial cultures. Moreover, treating oral LABP-66, vehicle, after onset paralysis resulted less These data suggest have potential limit This study highlights could serve as promising target for neuroprotection MS other neurodegenerative diseases. Further studies are needed better understand cell-specific mechanisms underlying neuroprotective response inflammation CNS.

Language: Английский

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The ELF3-TRIM22-MAVS signaling axis regulates type I interferon and antiviral responses

Journal of Virology, Journal Year: 2025, Volume and Issue: unknown

Published: March 31, 2025

ABSTRACT Activation of the innate immune response is essential for host cells to restrict dissemination invading viruses and other pathogens. Proteins belonging tripartite motif (TRIM) family are key effectors in antiviral immunity. Among these, TRIM22, a RING-type E3 ubiquitin ligase, has been recognized as significant regulator pathogenesis various diseases. In present study, we identified TRIM22 critical modulator mitochondrial signaling protein (MAVS) activation. Loss function led reduced production type I interferons (IFNs) viral infection such influenza A virus (IAV) or vesicular stomatitis (VSV), thereby facilitating replication. Mechanistically, was found enhance retinoic acid-inducible gene (RIG-I)-mediated through catalysis Lys63-linked polyubiquitination MAVS, which, turn, activated TANK-binding kinase 1 (TBK1)/interferon regulatory factor 3 (IRF3) pathway, driving IFN-β production. Additionally, shown inhibit assembly MAVS-NLRX1 inhibitory complex, further amplifying responses. Our findings also demonstrated that RNA upregulated expression via nuclear translocation ELF3, transcription activates expression. This loop underscores role modulating IFN providing insights into host’s defense mechanisms. research highlights potential targeting ELF3-TRIM22-MAVS axis therapeutic strategy enhancing immunity preventing infections. IMPORTANCE Interferon (IFN)-mediated responses crucial against foreign pathogens regulated by pathways. The family, its multifaceted roles regulation defense, plays part this process. our explored important helped regulate We enhances (MAVS), which producing interferons. Interestingly, discovered increases after an infection, due moved nucleus activate transcription. created feedback strengthens pathway. By uncovering these mechanisms, aimed understanding how system works provide could lead innovative therapies.

Language: Английский

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Mitochondria – the CEO of the cell

Journal of Cell Science, Journal Year: 2025, Volume and Issue: 138(9)

Published: May 1, 2025

As we have learned more about mitochondria over the past decades, including their essential cellular roles and how altered mitochondrial biology results in disease, it has become apparent that they are not just powerplants pumping out ATP at whim of cell. Rather, dynamic information energy processors play crucial directing dozens processes behaviors. They provide instructions to enact programs regulate various operations, such as complex metabolic networks, signaling innate immunity, even control cell fate, dictating when cells should divide, differentiate or die. To help current future generations biologists incorporate dynamic, multifaceted nature assimilate modern discoveries into scientific framework, need a 21st century 'rebranding'. In this Opinion article, argue be considered 'Chief Executive Organelle' - CEO

Language: Английский

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MicroRNA transcriptome analysis reveals the immune regulatory mechanism of Crassostrea hongkongesis against Vibrio harveyi infection

Fish & Shellfish Immunology, Journal Year: 2024, Volume and Issue: 145, P. 109354 - 109354

Published: Jan. 1, 2024

Language: Английский

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Implication of the LRR Domain in the Regulation and Activation of the NLRP3 Inflammasome

Cells, Journal Year: 2024, Volume and Issue: 13(16), P. 1365 - 1365

Published: Aug. 16, 2024

The NLRP3 inflammasome is a critical component of the innate immune response. activation tightly controlled process involving an initial priming to express NLRP3, pro-IL-1 β, and pro-IL-18, followed by signal. precise mechanism not fully understood due diverse range activators, yet it effectively orchestrates caspase-1, which subsequently triggers release proinflammatory cytokines IL-1β IL-18. dysregulation can lead variety inflammatory diseases, highlighting its significant role in response disease pathogenesis. divided into three domains: PYD, NACHT, LRR domains. This review focuses on domain detailing structural characteristics, function pathogen sensing, degradation process, involvement auto-inhibition activation. Additionally, we discuss impact mutations within found atypical Cryopyrin-Associated Periodic Syndromes (CAPS), clinical relevance this domain.

Language: Английский

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Evolutionary edge: NOD-like receptors in immunity

Biomedical Journal, Journal Year: 2024, Volume and Issue: 47(1), P. 100702 - 100702

Published: Jan. 30, 2024

This issue of the Biomedical Journal delves into multifaceted roles NOD-like receptors (NLRs) in immunity, examining their subfamilies and functions within innate adaptive autoimmune inflammatory conditions, mitophagy regulation. In this dynamics mRNA vaccines are explored, as well synergistic effects a ketogenic diet with anti-tumor therapies, curcumin RANKL osteoclastogenesis, validation rapid diagnostic test for an oral cancer biomarker. Additionally, advancements ocular care highlighted, featuring novel prodrug targeting corneal neovascularization, discussing efficacy dexamethasone implants against macular edema. Concluding, further insights impact sweetened foods on child development given.

Language: Английский

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NLRX1 Inhibits LPS-Induced Microglial Death via Inducing p62-Dependent HO-1 Expression, Inhibiting MLKL and Activating PARP-1

Antioxidants, Journal Year: 2024, Volume and Issue: 13(4), P. 481 - 481

Published: April 17, 2024

The activation of microglia and the production cytokines are key factors contributing to progressive neurodegeneration. Despite well-recognized neuronal programmed cell death regulated by microglial activation, themselves is less investigated. Nucleotide-binding oligomerization domain, leucine-rich repeat-containing X1 (NLRX1) functions as a scaffolding protein involved in various central nervous system diseases. In this study, we used SM826 cells understand role NLRX1 lipopolysaccharide (LPS)-induced death. We found LPS-induced blocked necrostatin-1 zVAD. Meanwhile, LPS can activate poly (ADP-ribose) polymerase-1 (PARP-1) reduce DNA damage induce heme oxygenase (HO)-1 expression counteract silencing PARP-1 inhibition olaparib enhance an additive manner. Less PARylation higher observed NLRX1-silencing cells. Moreover, HO-1 gene through p62-Keap1-Nrf2 axis attenuated silencing. addition, Nrf2-mediated positive feedback regulation p62 accordingly reduced Of note, does not affect cellular reactive oxygen species (ROS) but increases mixed lineage kinase domain-like pseudokinase (MLKL) necroptosis. blocks bafilomycin A1-induced activation. Taken together, for first time, demonstrate protecting from underlying protective mechanisms include upregulating via Nrf2-dependent downstream Keap1-Nrf2 axis, mediating repair ROS- autophagy-independent pathway, reducing MLKL

Language: Английский

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An NLR family member X1 mutation (p.Arg707Cys) suppresses hepatitis B virus infection in hepatocytes and favors the interaction of retinoic acid-inducible gene 1 with mitochondrial antiviral signaling protein

Archives of Virology, Journal Year: 2024, Volume and Issue: 169(11)

Published: Nov. 1, 2024

NLR family member X1 (NLRX1) is an important of the NOD-like receptor (NLR) and plays unique roles in immune system regulation. Patients with hepatitis B virus (HBV) infection are more likely to have NLRX1 mutation p.Arg707Cys than healthy individuals. It has been reported that increases rate HBV HepG2 cells expressing sodium taurocholate cotransporting polypeptide (NTCP). However, role (p.Arg707Cys) remains unclear. We constructed Huh7 stably overexpressed NTCP, using LV003 lentivirus. First, wild-type (WT) mutant (MT) overexpression plasmids were constructed. The MT plasmid contained a point at position 707 WT plasmid. Then, Huh7-NTCP transfected or plasmid, subsequent expression was analyzed real-time quantitative polymerase chain reaction (RT-qPCR) western blot. RNA levels determined RT-qPCR. HBsAg HBcAg confirmed immunohistochemically. Interferon alpha (IFN-α), interleukin 6 (IL-6), type I interferon beta (IFN-β) enzyme-linked immunosorbent assay kits. p-p65, p-interferon regulatory factor (IRF) 3, p-IRF7 examined interaction retinoic acid-inducible gene (RIG)-1/mitochondrial antiviral signaling (MAVS) protein by coimmunoprecipitation. IFN-α, IL-6, IFN-β dual luciferase reporter assay. RNA, HBsAg, infected higher those untransfected control group; these lower NLRX1. IFN-β, p-IRF3, cells. Moreover, competitively inhibited RIG1 binding MAVS, but reduced this inhibitory effect. In addition, decreased promoter activity IL-6. Our findings revealed inhibits anti-HBV ability hepatocytes suppresses activates IFN/nuclear κB pathway.

Language: Английский

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Identifying differentially expressed genes in goat mammary epithelial cells induced by overexpression of SOCS3 gene using RNA sequencing

Frontiers in Veterinary Science, Journal Year: 2024, Volume and Issue: 11

Published: May 21, 2024

The suppressor of cytokine signaling 3 (SOCS3) is a key molecule that regulates milk synthesis in dairy livestock. However, the molecular mechanism by which SOCS3 lipid goat remains unclear. This study aimed to screen for downstream genes associated with regulated mammary epithelial cells (GMECs) using RNA sequencing (RNA-seq). Goat overexpression vector (PC-SOCS3) and negative control (PCDNA3.1) were transfected into GMECs. Total from after was used RNA-seq, followed differentially expressed gene (DEG) analysis, functional enrichment network prediction. significantly inhibited triacylglycerol, total cholesterol, non-esterified fatty acids, accumulated droplets. In total, 430 DEGs identified, including 226 downregulated 204 upregulated genes, following overexpression. Functional annotation revealed mainly metabolism, cell proliferation, apoptosis. We found synthesis-related STAT2 FOXO6 , downregulated. addition, proliferation-related BCL2 MMP11 MMP13 upregulated, apoptosis-related CD40 conclusion, six identified as regulators Our results provide new candidate insights mechanisms involved goats.

Language: Английский

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