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Histology and Histopathology Mar 2022Adenosine deaminase (ADA) is a purine metabolism enzyme that catalyses the breakdown of adenosine and deoxyadenosine. The enzyme is important in several cellular... (Review)
Review
Adenosine deaminase (ADA) is a purine metabolism enzyme that catalyses the breakdown of adenosine and deoxyadenosine. The enzyme is important in several cellular processes, including the innate immune response and cellular differentiation, and it is also an important enzyme for the maintenance of brain homeostasis, in part due to its regulation of adenosine. Aberrant regulation of ADA enzyme activity has been linked to several neurodegenerative diseases and diseases that can result in neurological impairment. However, the mechanisms behind altered ADA regulation and how this leads to the development of neurological dysfunction are poorly characterised. This review summarises the current research on ADA and its role and regulation in disease pathology, with a focus on the central nervous system (CNS) and the neurodegenerative disease, amyotrophic lateral sclerosis (ALS).
Topics: Adenosine; Adenosine Deaminase; Amyotrophic Lateral Sclerosis; Brain; Humans; Neurodegenerative Diseases
PubMed: 34881804
DOI: 10.14670/HH-18-404 -
Nature Cell Biology Mar 2024Type 1 diabetes (T1D) is characterized by the destruction of pancreatic β-cells. Several observations have renewed the interest in β-cell RNA sensors and editors....
Type 1 diabetes (T1D) is characterized by the destruction of pancreatic β-cells. Several observations have renewed the interest in β-cell RNA sensors and editors. Here, we report that N-methyladenosine (mA) is an adaptive β-cell safeguard mechanism that controls the amplitude and duration of the antiviral innate immune response at T1D onset. mA writer methyltransferase 3 (METTL3) levels increase drastically in β-cells at T1D onset but rapidly decline with disease progression. mA sequencing revealed the mA hypermethylation of several key innate immune mediators, including OAS1, OAS2, OAS3 and ADAR1 in human islets and EndoC-βH1 cells at T1D onset. METTL3 silencing enhanced 2'-5'-oligoadenylate synthetase levels by increasing its mRNA stability. Consistently, in vivo gene therapy to prolong Mettl3 overexpression specifically in β-cells delayed diabetes progression in the non-obese diabetic mouse model of T1D. Mechanistically, the accumulation of reactive oxygen species blocked upregulation of METTL3 in response to cytokines, while physiological levels of nitric oxide enhanced METTL3 levels and activity. Furthermore, we report that the cysteines in position C276 and C326 in the zinc finger domains of the METTL3 protein are sensitive to S-nitrosylation and are important to the METTL3-mediated regulation of oligoadenylate synthase mRNA stability in human β-cells. Collectively, we report that mA regulates the innate immune response at the β-cell level during the onset of T1D in humans.
Topics: Animals; Humans; Mice; Adenosine Deaminase; Diabetes Mellitus, Type 1; Immunity, Innate; Insulin-Secreting Cells; Methyltransferases; Oxidation-Reduction
PubMed: 38409327
DOI: 10.1038/s41556-024-01368-0 -
Biochemical and Biophysical Research... Jan 2021The extensive sequence data generated from SARS-CoV-2 during the 2020 pandemic has facilitated the study of viral genome evolution over a brief period of time. This has... (Review)
Review
The extensive sequence data generated from SARS-CoV-2 during the 2020 pandemic has facilitated the study of viral genome evolution over a brief period of time. This has highlighted instances of directional mutation pressures exerted on the SARS-CoV-2 genome from host antiviral defense systems. In this brief review we describe three such human defense mechanisms, the apolipoprotein B mRNA editing catalytic polypeptide-like proteins (APOBEC), adenosine deaminase acting on RNA proteins (ADAR), and reactive oxygen species (ROS), and discuss their potential implications on SARS-CoV-2 evolution.
Topics: APOBEC Deaminases; Adenosine Deaminase; COVID-19; Gene Editing; Genome, Viral; Host-Pathogen Interactions; Humans; RNA-Binding Proteins; Reactive Oxygen Species; SARS-CoV-2
PubMed: 33234239
DOI: 10.1016/j.bbrc.2020.10.092 -
Andrology May 2023Adenosine deaminase domain containing 2 (ADAD2) is a testis-specific protein composed of a double-stranded RNA binding domain and a non-catalytic adenosine deaminase...
BACKGROUND
Adenosine deaminase domain containing 2 (ADAD2) is a testis-specific protein composed of a double-stranded RNA binding domain and a non-catalytic adenosine deaminase domain. A recent study showed that ADAD2 is indispensable for the male reproduction in mice. However, the detailed functions of ADAD2 remain elusive.
OBJECTIVES
This study aimed to investigate the cause of male sterility in Adad2 mutant mice and to understand the molecular functions of ADAD2.
MATERIALS AND METHODS
Adad2 homozygous mutant mouse lines, Adad2 and Adad2 , were generated by CRISPR/Cas9. Western blotting and immunohistochemistry were used to reveal the expression and subcellular localization of ADAD2. Co-immunoprecipitation tandem mass spectrometry was employed to determine the ADAD2-interacting proteins in mouse testes. RNA-sequencing analyses were carried out to analyze the transcriptome and PIWI-interacting RNA (piRNA) populations in wildtype and Adad2 mutant testes.
RESULTS
Adad2 and Adad2 mice exhibit male-specific sterility because of abnormal spermiogenesis. ADAD2 interacts with multiple RNA-binding proteins involved in piRNA biogenesis, including MILI, MIWI, RNF17, and YTHDC2. ADAD2 co-localizes and forms novel granules with RNF17 in spermatocytes. Ablation of ADAD2 impairs the formation of RNF17 granules, decreases the number of cluster-derived pachytene piRNAs, and increases expression of ping-pong-derived piRNAs.
DISCUSSION AND CONCLUSION
In collaboration with RNF17 and other RNA-binding proteins in spermatocytes, ADAD2 directly or indirectly functions in piRNA biogenesis.
Topics: Animals; Male; Mice; Piwi-Interacting RNA; RNA, Small Interfering; Adenosine Deaminase; Spermatogenesis; Testis; RNA-Binding Proteins
PubMed: 36698249
DOI: 10.1111/andr.13400 -
Frontiers in Public Health 2022Abdominal tuberculosis (TB) is a common type of extrapulmonary TB with an insidious onset and non-specific symptoms. Adenosine deaminase (ADA) levels increase rapidly in... (Meta-Analysis)
Meta-Analysis
BACKGROUND AND AIM
Abdominal tuberculosis (TB) is a common type of extrapulmonary TB with an insidious onset and non-specific symptoms. Adenosine deaminase (ADA) levels increase rapidly in the early stages of abdominal TB. However, it remains unclear whether ADA serves as a diagnostic marker for abdominal TB.
METHODS
We performed a systematic literature search for relevant articles published in PubMed, Web of Science, Cochrane Library, and Embase up to April 2022. First, we used the Quality Assessment of Diagnostic Accuracy Studies tool-2 (QUADAS-2), to evaluate the quality of the included articles. Bivariate and hierarchical summary receiver operating characteristic (HSROC) models were then utilized to analyze pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR) and area under the receiver operating characteristic curve (AUROC). In addition, we explored a subgroup analysis for potential heterogeneity and publication bias among the included literature.
RESULTS
Twenty-four articles (3,044 participants, 3,044 samples) which met the eligibility criteria were included in this study. The pooled sensitivity and specificity of ADA for abdominal TB detection were 93% [95% confidence interval (CI): 0.89-0.95] and 95% (95% CI: 0.93-0.96), respectively. PLR and NLR were 18.6 (95% CI: 14.0-24.6) and 0.08 (95% CI: 0.05-0.12), respectively. DOR and AUROC were 236 (95% CI: 134-415) and 0.98 (95% CI: 0.96-0.99), respectively. Furthermore, no heterogeneity or publication bias was found.
CONCLUSIONS
Our meta-analysis found ADA to be of excellent diagnostic value for abdominal TB and could be used as an auxiliary diagnostic tool.
SYSTEMATIC REVIEW REGISTRATION
https://www.crd.york.ac.uk/prospero/, identifier: CRD42022297931.
Topics: Adenosine Deaminase; Humans; ROC Curve; Sensitivity and Specificity; Tuberculosis
PubMed: 36211645
DOI: 10.3389/fpubh.2022.938544 -
Genes Jul 2020Major depressive disorder (MDD) is a major health problem with significant limitations in functioning and well-being. The World Health Organization (WHO) evaluates MDD... (Review)
Review
Major depressive disorder (MDD) is a major health problem with significant limitations in functioning and well-being. The World Health Organization (WHO) evaluates MDD as one of the most disabling disorders in the world and with very high social cost. Great attention has been given to the study of the molecular mechanism underpinning MDD at the genetic, epigenetic and proteomic level. However, the importance of RNA modifications has attracted little attention until now in this field. RNA molecules are extensively and dynamically altered by a variety of mechanisms. Similar to "epigenomic" changes, which modify DNA structure or histones, RNA alterations are now termed "epitranscriptomic" changes and have been predicted to have profound consequences for gene expression and cellular functionality. Two of these modifications, adenosine to inosine (A-to-I) RNA editing and m6A methylations, have fascinated researchers over the last years, showing a new level of complexity in gene expression. In this review, we will summary the studies that focus on the role of RNA editing and m6A methylation in MDD, trying to underline their potential breakthroughs and pitfalls.
Topics: Adenosine Deaminase; Animals; Epigenome; Humans; Methyltransferases; Mood Disorders; RNA Editing
PubMed: 32752036
DOI: 10.3390/genes11080872 -
Nucleic Acids Research Aug 2023Site-directed RNA base editing enables the transient and dosable change of genetic information and represents a recent strategy to manipulate cellular processes, paving...
Site-directed RNA base editing enables the transient and dosable change of genetic information and represents a recent strategy to manipulate cellular processes, paving ways to novel therapeutic modalities. While tools to introduce adenosine-to-inosine changes have been explored quite intensively, the engineering of precise and programmable tools for cytidine-to-uridine editing is somewhat lacking behind. Here we demonstrate that the cytidine deaminase domain evolved from the ADAR2 adenosine deaminase, taken from the RESCUE-S tool, provides very efficient and highly programmable editing when changing the RNA targeting mechanism from Cas13-based to SNAP-tag-based. Optimization of the guide RNA chemistry further allowed to dramatically improve editing yields in the difficult-to-edit 5'-CCN sequence context thus improving the substrate scope of the tool. Regarding editing efficiency, SNAP-CDAR-S outcompeted the RESCUE-S tool clearly on all tested targets, and was highly superior in perturbing the β-catenin pathway. NGS analysis showed similar, moderate global off-target A-to-I and C-to-U editing for both tools.
Topics: RNA; Base Sequence; Gene Editing; RNA Editing; Adenosine Deaminase
PubMed: 37462074
DOI: 10.1093/nar/gkad598 -
Cell Reports Jul 2023Variants of the RNA-editing enzyme ADAR1 cause Aicardi-Goutières syndrome (AGS), in which severe inflammation occurs in the brain due to innate immune activation. Here,...
Variants of the RNA-editing enzyme ADAR1 cause Aicardi-Goutières syndrome (AGS), in which severe inflammation occurs in the brain due to innate immune activation. Here, we analyze the RNA-editing status and innate immune activation in an AGS mouse model that carries the Adar P195A mutation in the N terminus of the ADAR1 p150 isoform, the equivalent of the P193A human Zα variant causal for disease. This mutation alone can cause interferon-stimulated gene (ISG) expression in the brain, especially in the periventricular areas, reflecting the pathologic feature of AGS. However, in these mice, ISG expression does not correlate with an overall decrease in RNA editing. Rather, the enhanced ISG expression in the brain due to the P195A mutant is dose dependent. Our findings indicate that ADAR1 can regulate innate immune responses through Z-RNA binding without changing overall RNA editing.
Topics: Humans; Animals; Mice; RNA; RNA Editing; Signal Transduction; Interferons; Brain; Mutation; Adenosine Deaminase
PubMed: 37421629
DOI: 10.1016/j.celrep.2023.112733 -
Scientific Reports Jul 2021Rheumatoid Arthritis (RA) is a chronic autoimmune disease associated with inflammation and joint remodeling. Adenosine deaminase (ADA), a risk factor in RA, degrades...
Rheumatoid Arthritis (RA) is a chronic autoimmune disease associated with inflammation and joint remodeling. Adenosine deaminase (ADA), a risk factor in RA, degrades adenosine, an anti-inflammatory molecule, resulting in an inflammatory bias. We present an integrative analysis of clinical data, cytokines, serum metabolomics in RA patients and mechanistic studies on ADA-mediated effects on in vitro cell culture models. ADA activity differentiated patients into low and high ADA sets. The levels of the cytokines TNFα, IFNγ, IL-10, TGFβ and sRANKL were elevated in RA and more pronounced in high ADA sets. Serum metabolomic analysis shows altered metabolic pathways in RA which were distinct between low and high ADA sets. Comparative analysis with previous studies shows similar pathways are modulated by DMARDs and biologics. Random forest analysis distinguished RA from control by methyl-histidine and hydroxyisocaproic acid, while hexose-phosphate and fructose-6-phosphate distinguished high ADA from low ADA. The deregulated metabolic pathways of High ADA datasets significantly overlapped with high ADA expressing PBMCs GEO transcriptomics dataset. ADA induced the death of chondrocytes, synoviocyte proliferation, both inflammation in macrophages and their differentiation into osteoclasts and impaired differentiation of mesenchymal stem cells to osteoblasts and mineralization. PBMCs expressing elevated ADA had increased expression of cytokines and P2 receptors compared to synovial macrophages which has low expression of ADA. Our data demonstrates increased cytokine levels and distinct metabolic signatures of RA based on the ADA activity, suggests an important role for ADA in the pathophysiology of RA joints and as a potential marker and therapeutic target in RA patients.
Topics: Adenosine Deaminase; Arthritis, Rheumatoid; Autoimmune Diseases; Biomarkers; Cytokines; Female; Humans; Inflammation; Leukocytes, Mononuclear; Macrophages; Male; Middle Aged; Osteoclasts; Synovial Fluid
PubMed: 34301999
DOI: 10.1038/s41598-021-94607-5 -
Metabolism: Clinical and Experimental Jun 2023Folate (FA) is an essential cofactor in the one-carbon (1C) metabolic pathway and participates in amino acid metabolism, purine and thymidylate synthesis, and DNA...
BACKGROUND
Folate (FA) is an essential cofactor in the one-carbon (1C) metabolic pathway and participates in amino acid metabolism, purine and thymidylate synthesis, and DNA methylation. FA metabolism has been reported to play an important role in viral replications; however, the roles of FA metabolism in the antiviral innate immune response are unclear.
OBJECTIVE
To evaluate the potential regulatory role of FA metabolism in antiviral innate immune response, we establish the model of FA deficiency (FAD) in vitro and in vivo. The molecular and functional effects of FAD on 2'-5'-oligoadenylate synthetases (OAS)-associated antiviral innate immunity pathways were assessed; and the potential relationship between FA metabolism and the axis of adenosine deaminases acting on RNA 3 (ADAR3)/endogenous double-stranded RNA (dsRNA)/OAS was further explored in the present study, as well as the potential translatability of these findings in vivo.
METHODS
FA-free RPMI 1640 medium and FA-free feed were used to establish the model of FAD in vitro and in vivo. And FA and homocysteine (Hcy) concentrations in cell culture supernatants and serum were used for FAD model evaluation. Ribonucleoprotein immunoprecipitation assay was used to enrich endogenous dsRNA, and dot-blot was further used for quantitative analysis of endogenous dsRNA. Western-blot assay, RNA isolation and quantitative real-time PCR, immunofluorescence assay, and other molecular biology techniques were used for exploring the potential mechanisms.
RESULTS
In this study, we observed that FA metabolism negatively regulated OAS-mediated antiviral innate immune response. Mechanistically, FAD induced ADAR3, which interacted with endogenous dsRNA, to inhibit deaminated adenosine (A) being converted into inosine (I), leading to the cytoplasmic accumulation of dsRNA. Furthermore, endogenous dsRNA accumulated in cytoplasm triggered the host immune activation, thus promoting the expression of OAS2 to suppress the replication of viruses. Additionally, injection of 8-Azaadenosine to experimental animals, an A-to-I editing inhibitor, efficiently enhanced OAS-mediated antiviral innate immune response to reduce the viral burden in vivo.
CONCLUSIONS
Taken together, our present study provided a new perspective to illustrate a relationship between FA metabolism and the axis of ADAR3/endogenous dsRNA/OAS, and a new insight for the treatment of RNA viral infectious diseases by targeting the axis of ADAR3/endogenous dsRNA/OAS.
Topics: Animals; Adenosine; Antiviral Agents; Immunity, Innate; RNA, Double-Stranded; RNA-Binding Proteins; Adenosine Deaminase
PubMed: 36822494
DOI: 10.1016/j.metabol.2023.155526