RNase T2 restricts TLR13-mediated autoinflammation in vivo

The Journal of Experimental Medicine, Journal Year: 2025, Volume and Issue: 222(3)

Published: Jan. 24, 2025

RNA-sensing TLRs are strategically positioned in the endolysosome to detect incoming nonself RNA. RNase T2 plays a critical role processing long, structured RNA into short oligoribonucleotides that engage TLR7 or TLR8. In addition its positive regulatory role, also restricts recognition through unknown mechanisms, as patients deficient suffer from neuroinflammation. Consistent with this, mice lacking exhibit interferon-dependent neuroinflammation, impaired hematopoiesis, and splenomegaly. However, mechanism by which deficiency unleashes inflammation vivo remains unknown. Here, we report inflammatory phenotype found Rnaset2−/− is completely reversed absence of TLR13, suggesting aberrant accumulation an ligand for this receptor. Interestingly, TLR13-driven fully present germ-free mice, limiting erroneous TLR13 activation yet unidentified endogenous ligand. These results establish potential self-sensor kept check T2.

Language: Английский

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Small RNA and Toll-like receptor interactions: origins and disease mechanisms

Trends in Biochemical Sciences, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 1, 2025

Language: Английский

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PLD3 and PLD4 synthesize S,S-BMP, a key phospholipid enabling lipid degradation in lysosomes

Cell, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 1, 2024

Language: Английский

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RNA recognition in toll-like receptor signaling

Current Opinion in Structural Biology, Journal Year: 2024, Volume and Issue: 88, P. 102913 - 102913

Published: Aug. 22, 2024

RNA, either from invading pathogens or within the hosts, is one of principal PAMPs (pathogen-associated molecular patterns). Toll-like receptors (TLRs) and other innate immune system exist that detect immunostimulatory RNA including double single stranded then induce cytokine-mediated antiviral proinflammatory responses. Recent years have seen remarkable progress in biochemical, immunological, structural biological studies on TLRs, opening new avenues for TLR signaling. In this review, we highlight our current understanding RNA- sensing TLRs discuss regulatory mechanisms normally prevent inappropriate responses to self.

Language: Английский

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RNA sensing at the crossroads of autoimmunity and autoinflammation

RNA, Journal Year: 2025, Volume and Issue: unknown, P. rna.080304.124 - rna.080304.124

Published: Jan. 8, 2025

Immune-mediated diseases are common in humans. The immune system is a complex host defense that evolved to protect us from pathogens, but also plays an important role homeostatic processes, removing dead or senescent cells, and participating tumor surveillance. human has two arms: the older innate system, newer adaptive system. Sensing of foreign RNA critical system’s ability recognize especially viral infections. However, sensors strongly implicated autoimmune autoinflammatory diseases, highlighting importance balancing pathogen recognition with tolerance RNAs can resemble their counterparts. We describe how bind ligands, this binding coupled upregulation Type I interferon-stimulated genes, ways which mutations genes play roles homeostasis have been linked diseases.

Language: Английский

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AMPylation regulates PLD3 processing.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 9, 2025

The 5’-3’ exonuclease phospholipase D3 (PLD3) is a single-pass transmembrane protein undergoing sequential post-translational modifications (PTM) by N -glycosylation, AMPylation and proteolytic cleavage. substrates of PLD3 activity are single-stranded DNAs RNAs, which act as ligands for Toll-like receptors (TLRs) trigger downstream pro-inflammatory response. Although has primarily been studied in immune cells, recent findings indicate its enrichment neurons, where it plays role regulating axonal fitness Alzheimer’s disease (AD). However, the regulatory mechanisms governing processing into catalytically active soluble form functional roles both neuronal cells remain unclear. Here, we describe implications AMPylation, direct interaction with adenylyltransferase FICD, changes Parkinson’s (PD) patient-derived neurons. We identified sites within proteins’ region show that mutation these lead to loss catalytic activity. FICD AMP-transferase accelerates degradation induces cellular stress Furthermore, depletion two human AMP-transferases SelO point towards complex network AMPylation. Together, our demonstrate critical regulation provide new insights protein’s transport localization lysosomes. observation PD-derived neurons altered compared healthy further highlights neurodegenerative diseases.

Language: Английский

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ZUGC-RNA degradation generates immunosuppressor to evade immune responses in eukaryotes

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 28, 2025

Abstract Among the hundreds of modified nucleosides identified in terrestrial life, 2-amino-6-aminopurine (Z) is widely recognized as a prominent purine. Recently, RNA written with ZUGC alphabet shows significant potential therapeutics synthetic biosystem. Here, we demonstrate that ZUGC-RNA can evade immune recognition eukaryotes, independent factors such length, sequence, 5’-triphosphate, uridine, and secondary structure. Notably, discovered both degradation metabolites Z-nucleotides function immunosuppressors, silencing TLR7 sensing to block responses. This mechanism differs from pseudo-uridine (Ψ) currently use. ZUGC-RNAs also broad applicability across multiple neural cell types. Our findings provide valuable insights for developing more tolerable RNA-based drugs designing immunomodulators targeting TLR7. In addition prebiotic relevance Z, our finding not only contributes understanding world hypothesis but provides new into exploration origin life.

Language: Английский

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Nucleic acid triggers of autoimmunity and autoinflammation

Current Opinion in Immunology, Journal Year: 2025, Volume and Issue: 93, P. 102535 - 102535

Published: Jan. 30, 2025

Language: Английский

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Insect-specific virus platforms for arbovirus vaccine development

Frontiers in Immunology, Journal Year: 2025, Volume and Issue: 16

Published: March 14, 2025

Certain insect-specific viruses (ISVs), specifically the mosquito alphaviruses, Eilat and Yada viruses, orthoflaviviruses, Binjari, Aripo, YN15-283-02 Chaoyang have emerged as potential platforms for generation of whole virus vaccines human veterinary applications. These ISVs are remarkably tolerant substitution their structural polyproteins with those alphaviruses orthoflaviviruses that pathogenic in humans and/or animals. The resulting ISV-based chimeric been evaluated mouse models demonstrated safety efficacy non-human primates, crocodiles pigs. Targets include chikungunya, Venezuelan eastern equine encephalitis, dengue, Zika, yellow fever, Japanese encephalitis West Nile viruses. provide authentically folded tertiary quaternary virion particle structures to immune system, a key feature induction protective antibody responses. manufactured C6/36 or C7-10 cell lines, where they grow high titers, but do not replicate vertebrate vaccine recipients. This review discusses progress these emerging technologies addresses challenges related adjuvanting, safety, manufacturing.

Language: Английский

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Cytosolic nucleic acid sensing as driver of critical illness: mechanisms and advances in therapy

Signal Transduction and Targeted Therapy, Journal Year: 2025, Volume and Issue: 10(1)

Published: March 19, 2025

Abstract Nucleic acids from both self- and non-self-sources act as vital danger signals that trigger immune responses. Critical illnesses such acute respiratory distress syndrome, sepsis, trauma ischemia lead to the aberrant cytosolic accumulation massive release of nucleic are detected by antiviral innate receptors in endosome or cytosol. Activation for deoxyribonucleic ribonucleic triggers inflammation, a major contributor morbidity mortality critically ill patients. In past decade, there has been growing recognition therapeutic potential targeting acid sensing critical care. This review summarizes current knowledge ischemia. Given extensive research on common pathological conditions like cancer, autoimmune disorders, metabolic disorders aging, we provide comprehensive summary beyond illness offer insights may inform its role conditions. Additionally, discuss strategies specifically target sensing. By examining sources, sensor activation function, well impact regulating these pathways across various diseases, highlight driving illness.

Language: Английский

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