The competitive landscape of the dsRNA world

Molecular Cell, Год журнала: 2023, Номер 84(1), С. 107 - 119

Опубликована: Дек. 19, 2023

Язык: Английский

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ADAR1: from basic mechanisms to inhibitors

Trends in Cell Biology, Год журнала: 2024, Номер unknown

Опубликована: Июль 1, 2024

Adenosine deaminase acting on RNA 1 (ADAR1) converts adenosine to inosine in double-stranded (dsRNA) molecules, a process known as A-to-I editing. ADAR1 deficiency humans and mice results profound inflammatory diseases characterised by the spontaneous induction of innate immunity. In cells lacking ADAR1, unedited RNAs activate sensors. These include melanoma differentiation-associated gene 5 (MDA5) that induces expression cytokines, particularly type I interferons (IFNs), protein kinase R (PKR), oligoadenylate synthase (OAS), Z-DNA/RNA binding (ZBP1). Immunogenic 'defused' may transcripts from repetitive elements other long duplex RNAs. Here, we review these recent fundamental discoveries discuss implications for human diseases. Some tumours depend escape immune surveillance, opening possibility unleashing anticancer therapies with inhibitors.

Язык: Английский

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Multifaceted roles of RNA editing enzyme ADAR1 in innate immunity

RNA, Год журнала: 2024, Номер 30(5), С. 500 - 511

Опубликована: Март 26, 2024

Innate immunity must be tightly regulated to enable sensitive pathogen detection while averting autoimmunity triggered by pathogen-like host molecules. A hallmark of viral infection, double-stranded RNAs (dsRNAs) are also abundantly encoded in mammalian genomes, necessitating surveillance mechanisms distinguish “self” from “nonself.” ADAR1, an RNA editing enzyme, has emerged as essential safeguard against dsRNA-induced autoimmunity. By converting adenosines inosines (A-to-I) long dsRNAs, ADAR1 covalently marks endogenous thereby blocking the activation cytoplasmic dsRNA sensor MDA5. Moreover, beyond its function, binding impedes innate immune sensors PKR and ZBP1. Recent landmark studies underscore utility silencing for cancer immunotherapy, exploiting ADAR1-dependence developed certain tumors unleash antitumor response. In this perspective, we summarize genetic mechanistic evidence ADAR1's multipronged role suppressing dsRNA-mediated explore evolving roles immuno-oncology target.

Язык: Английский

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A Wonderful Journey: The Diverse Roles of Adenosine Deaminase Action on RNA 1 (ADAR1) in Central Nervous System Diseases

CNS Neuroscience & Therapeutics, Год журнала: 2025, Номер 31(1)

Опубликована: Янв. 1, 2025

ABSTRACT Background Adenosine deaminase action on RNA 1 (ADAR1) can convert the adenosine in double‐stranded (dsRNA) molecules into inosine a process known as A‐to‐I editing. ADAR1 regulates gene expression output by interacting with and other proteins; plays important roles development, including growth; is linked to innate immunity, tumors, central nervous system (CNS) diseases. Results In recent years, role of tumors has been widely discussed, but its CNS diseases not reviewed. It worth noting that studies have shown great potential treatment neurodegenerative diseases, mechanisms are still unclear. Therefore, it necessary elaborate Conclusions Here, we focus effects such Aicardi–AicardiGoutières syndrome, Alzheimer's disease, Parkinson's glioblastoma, epilepsy, amyotrophic lateral sclerosis, autism. We also evaluate impact ADAR1‐based strategies these particular development new technologies microRNAs, nanotechnology, editing, stem cell therapy. hope provide directions insights for future editing technology brain science

Язык: Английский

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Adenosine deaminase and deoxyadenosine regulate intracellular immune response in C. elegans

iScience, Год журнала: 2025, Номер 28(3), С. 111950 - 111950

Опубликована: Фев. 4, 2025

Adenosine deaminase (ADA) and purine nucleoside phosphorylase (PNP) are enzymes in the salvage pathway, which recycles purines to meet cellular demands. Mutations of these humans cause inflammatory immunodeficiency syndromes, but mechanisms not well understood. Prior work nematode Caenorhabditis elegans demonstrated that loss PNP ortholog PNP-1 induced an immune response called intracellular pathogen (IPR). Here, we show enzyme upstream ADAH-1 (ADA homolog) also induces IPR promotes resistance against pathogens. Unlike PNP-1, is essential for organismal development. Importantly, find supplementation deoxyadenosine, a substrate ADA, pathogens C. elegans, finding extend human cells. Thus, mutations ADA induce innate immunity through increased phenomenon conserved from humans.

Язык: Английский

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RNA editing and immune control: from mechanism to therapy

Current Opinion in Genetics & Development, Год журнала: 2024, Номер 86, С. 102195 - 102195

Опубликована: Апрель 21, 2024

Язык: Английский

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Mouse models for understanding physiological functions of ADARs

Methods in enzymology on CD-ROM/Methods in enzymology, Год журнала: 2025, Номер unknown, С. 153 - 185

Опубликована: Янв. 1, 2025

Язык: Английский

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

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Янв. 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.

Язык: Английский

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Designer antisense circRNAGFP reduces GFP abundance in Arabidopsis protoplasts in a sequence-specific manner, independent of RNAi pathways

Research Square (Research Square), Год журнала: 2025, Номер unknown

Опубликована: Март 24, 2025

Circular RNAs (circRNAs) are single-stranded RNA molecules characterised by their covalently closed structure and emerging as key regulators of cellular processes in mammals, including gene expression, protein function immune responses. Recent evidence suggests that circRNAs also play significant roles plants, influencing development, nutrition, biotic stress resistance, abiotic tolerance. However, the potential to modulate target abundance plants remains largely unexplored. In this study, we investigated designer using Arabidopsis a model system. We demonstrate treatment with 50 nt circRNA_GFP, containing 30 GFP antisense sequence stretch, results reduced reporter dose- sequence-dependent manner. Notably, open isoform circRNA_GFP had little effect on abundance, indicating importance circular structure. Additionally, mutants defective interference (RNAi), suggesting circRNA activity is independent RNAi pathway. show circRNA, unlike dsRNA, does not induce pattern-triggered immunity (PTI) plants. Findings proof-of-principle study together crucial first steps understanding versatile tools for modulating expression offer exciting prospects application agronomy, particularly enhancing crop traits through metabolic pathway manipulation.

Язык: Английский

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ADAR1 p150 prevents HSV-1 from triggering PKR/eIF2α-mediated translational arrest and is required for efficient viral replication

PLoS Pathogens, Год журнала: 2025, Номер 21(4), С. e1012452 - e1012452

Опубликована: Апрель 8, 2025

Adenosine deaminase acting on dsRNA 1 (ADAR1) catalyzes the deamination of adenosines to inosines in double-stranded RNAs (dsRNA) and regulates innate immunity by preventing hyperactivation cytosolic sensors such as MDA5, PKR or ZBP1. ADAR1 has been shown exert pro- antiviral, editing-dependent editing-independent functions viral infections, but little is known about its function herpesvirus replication. We now demonstrate that herpes simplex virus (HSV-1) hyperactivates absence ADAR1, resulting eIF2α mediated translational arrest reduced Silencing inhibition downstream effectors (ICP34.5) pharmacological (ISRIB) inhibitors rescues replication ADAR1-deficient cells. Upon infection, p150 interacts with prevents hyperactivation. Our findings an important proviral factor raises activation threshold for immunity.

Язык: Английский

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