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Accounts of Chemical Research Nov 2023The adenosine deaminase acting on RNA (ADAR) enzymes that catalyze the conversion of adenosine to inosine in double-stranded (ds)RNA are evolutionarily conserved and are...
The adenosine deaminase acting on RNA (ADAR) enzymes that catalyze the conversion of adenosine to inosine in double-stranded (ds)RNA are evolutionarily conserved and are essential for many biological functions including nervous system function, hematopoiesis, and innate immunity. Initially it was assumed that the wide-ranging biological roles of ADARs are due to inosine in mRNA being read as guanosine by the translational machinery, allowing incomplete RNA editing in a target codon to generate two different proteins from the same primary transcript. In humans, there are approximately seventy-six positions that undergo site-specific editing in tissues at greater than 20% efficiency that result in recoding. Many of these transcripts are expressed in the central nervous system (CNS) and edited by ADAR2. Exploiting mouse genetic models revealed that transgenic mice lacking the gene encoding Adar2 die within 3 weeks of birth. Therefore, the role of ADAR2 in generating protein diversity in the nervous system is clear, but why is ADAR RNA editing activity essential in other biological processes, particularly editing mainly involving ADAR1? ADAR1 edits human transcripts having embedded Alu element inverted repeats (AluIRs), but the link from this activity to innate immunity activation was elusive. Mice lacking the gene encoding Adar1 are embryonically lethal, and a major breakthrough was the discovery that the role of Adar1 in innate immunity is due to its ability to edit such repetitive element inverted repeats which have the ability to form dsRNA in transcripts. The presence of inosine prevents activation of the dsRNA sensor melanoma differentiation-associated protein 5 (Mda5). Thus, inosine helps the cell discriminate self from non-self RNA, acting like a barcode on mRNA. As innate immunity is key to many different biological processes, the basis for this widespread biological role of the ADAR1 enzyme became evident.Our group has been studying ADARs from the outset of research on these enzymes. In this Account, we give a historical perspective, moving from the initial purification of ADAR1 and ADAR2 and cloning of their encoding genes up to the current research focus in the field and what questions still remain to be addressed. We discuss the characterizations of the proteins, their localizations, posttranslational modifications, and dimerization, and how all of these affect their biological activities. Another aspect we explore is the use of mouse and genetic models to study ADAR functions and how these were crucial in determining the biological functions of the ADAR proteins. Finally, we describe the severe consequences of rare mutations found in the human genes encoding ADAR1 and ADAR2.
Topics: Animals; Mice; Humans; Adenosine Deaminase; RNA, Double-Stranded; Immunity, Innate; RNA, Messenger; Inosine
PubMed: 37906879
DOI: 10.1021/acs.accounts.3c00433 -
Emerging Microbes & Infections Dec 2023Cytokine dynamics in patients with coronavirus disease 2019 (COVID-19) have been studied in blood but seldomly in respiratory specimens. We studied different cell...
Correlations of Myeloperoxidase (MPO), Adenosine deaminase (ADA), C-C motif chemokine 22 (CCL22), Tumour necrosis factor alpha (TNFα) and Interleukin-6 (IL-6) mRNA expression in the nasopharyngeal specimens with the diagnosis and severity of SARS-CoV-2 infections.
Cytokine dynamics in patients with coronavirus disease 2019 (COVID-19) have been studied in blood but seldomly in respiratory specimens. We studied different cell markers and cytokines in fresh nasopharyngeal swab specimens for the diagnosis and for stratifying the severity of COVID-19. This was a retrospective case-control study comparing Myeloperoxidase (MPO), Adenosine deaminase (ADA), C-C motif chemokine ligand 22 (CCL22), Tumour necrosis factor alpha (TNFα) and Interleukin-6 (IL-6) mRNA expression in 490 (327 patients and 163 control) nasopharyngeal specimens from 317 (154 COVID-19 and 163 control) hospitalized patients. Of the 154 COVID-19 cases, 46 died. Both total and normalized MPO, ADA, CCL22, TNFα, and IL-6 mRNA expression levels were significantly higher in the nasopharyngeal specimens of infected patients when compared with controls, with ADA showing better performance (OR 5.703, 95% CI 3.424-9.500, < 0.001). Receiver operating characteristics (ROC) curve showed that the cut-off value of normalized ADA mRNA level at 2.37 × 10 had a sensitivity of 81.8% and specificity of 83.4%. While patients with severe COVID-19 had more respiratory symptoms, and elevated lactate dehydrogenase, multivariate analysis showed that severe COVID-19 patients had lower CCL22 mRNA (OR 0.211, 95% CI 0.060-0.746, = 0.016) in nasopharyngeal specimens, while lymphocyte count, C-reactive protein, and viral load in nasopharyngeal specimens did not correlate with disease severity. In summary, ADA appears to be a better biomarker to differentiate between infected and uninfected patients, while CCL22 has the potential in stratifying the severity of COVID-19.
Topics: Humans; COVID-19; Interleukin-6; Tumor Necrosis Factor-alpha; Retrospective Studies; Adenosine Deaminase; Case-Control Studies; Peroxidase; Ligands; SARS-CoV-2; Cytokines; Chemokines; Nasopharynx; Chemokine CCL22
PubMed: 36482706
DOI: 10.1080/22221751.2022.2157338 -
Frontiers in Immunology 2019Specialized receptors that recognize molecular patterns such as double stranded RNA duplexes-indicative of viral replication-are potent triggers of the innate immune... (Review)
Review
Specialized receptors that recognize molecular patterns such as double stranded RNA duplexes-indicative of viral replication-are potent triggers of the innate immune system. Although their activation is beneficial during viral infection, RNA transcribed from endogenous mobile genetic elements may also act as ligands potentially causing autoimmunity. Recent advances indicate that the adenosine deaminase ADAR1 through RNA editing is involved in dampening the canonical antiviral RIG-I-like receptor-, PKR-, and OAS-RNAse L pathways to prevent autoimmunity. However, this inhibitory effect must be overcome during viral infections. In this review we discuss ADAR1's critical role in balancing immune activation and self-tolerance.
Topics: Adenosine Deaminase; Animals; Cell Cycle Checkpoints; Cytoplasm; DEAD Box Protein 58; Disease Susceptibility; Endoribonucleases; Humans; Immunity, Innate; Interferons; RNA Editing; RNA-Binding Proteins; Signal Transduction; eIF-2 Kinase
PubMed: 31404141
DOI: 10.3389/fimmu.2019.01763 -
Blood Aug 2022
Topics: Adenosine Deaminase; Humans; Severe Combined Immunodeficiency
PubMed: 35980680
DOI: 10.1182/blood.2022017722 -
Molecules (Basel, Switzerland) Apr 2017Adenosine is readily available to the glandular epithelium of the stomach. Formed continuously in intracellular and extracellular locations, it is notably produced from...
Adenosine is readily available to the glandular epithelium of the stomach. Formed continuously in intracellular and extracellular locations, it is notably produced from ATP released in enteric cotransmission. Adenosine analogs modulate chloride secretion in gastric glands and activate acid secretion in isolated parietal cells through A adenosine receptor (A2BR) binding. A functional link between surface A2BR and adenosine deaminase (ADA) was found in parietal cells, but whether this connection is a general feature of gastric mucosa cells is unknown. Here we examine whether A2BR is expressed at the membrane of histamine-producing enterochromaffin-like (ECL) cells, the major endocrine cell type in the oxyntic mucosa, and if so, whether it has a vicinity relationship with ADA. We used a highly homogeneous population of rabbit ECL cells (size 7.5-10 µm) after purification by elutriation centrifugation. The surface expression of A2BR and ADA proteins was assessed by flow cytometry and confocal microscopy. Our findings demonstrate that A2BR and ADA are partially coexpressed at the gastric ECL cell surface and that A2BR is functional, with regard to binding of adenosine analogs and adenylate cyclase activation. The physiological relevance of A2BR and ADA association in regulating histamine release is yet to be explained.
Topics: Adenosine Deaminase; Animals; Biomarkers; Enterochromaffin-like Cells; Flow Cytometry; Gastric Mucosa; Gene Expression; Rabbits; Receptor, Adenosine A2B
PubMed: 28417934
DOI: 10.3390/molecules22040625 -
Genome Biology Dec 2012Adenosine to inosine (A-to-I) RNA editing is a post-transcriptional process by which adenosines are selectively converted to inosines in double-stranded RNA (dsRNA)... (Review)
Review
Adenosine to inosine (A-to-I) RNA editing is a post-transcriptional process by which adenosines are selectively converted to inosines in double-stranded RNA (dsRNA) substrates. A highly conserved group of enzymes, the adenosine deaminase acting on RNA (ADAR) family, mediates this reaction. All ADARs share a common domain architecture consisting of a variable number of amino-terminal dsRNA binding domains (dsRBDs) and a carboxy-terminal catalytic deaminase domain. ADAR family members are highly expressed in the metazoan nervous system, where these enzymes predominantly localize to the neuronal nucleus. Once in the nucleus, ADARs participate in the modification of specific adenosines in pre-mRNAs of proteins involved in electrical and chemical neurotransmission, including pre-synaptic release machineries, and voltage- and ligand-gated ion channels. Most RNA editing sites in these nervous system targets result in non-synonymous codon changes in functionally important, usually conserved, residues and RNA editing deficiencies in various model organisms bear out a crucial role for ADARs in nervous system function. Mutation or deletion of ADAR genes results in striking phenotypes, including seizure episodes, extreme uncoordination, and neurodegeneration. Not only does the process of RNA editing alter important nervous system peptides, but ADARs also regulate gene expression through modification of dsRNA substrates that enter the RNA interference (RNAi) pathway and may then act at the chromatin level. Here, we present a review on the current knowledge regarding the ADAR protein family, including evolutionary history, key structural features, localization, function and mechanism.
Topics: Adenosine Deaminase; Animals; Evolution, Molecular; Humans; Multigene Family; RNA Editing; RNA Splicing
PubMed: 23273215
DOI: 10.1186/gb-2012-13-12-252 -
The European Respiratory Journal Apr 1996
Topics: Adenosine Deaminase; Communicable Diseases; Humans; Immunity; Isoenzymes
PubMed: 8726922
DOI: 10.1183/09031936.96.09040632 -
RNA (New York, N.Y.) Sep 2017ADAR RNA editing enzymes (denosine eminases acting on NA) that convert adenosine bases to inosines were first identified biochemically 30 years ago. Since then, studies... (Review)
Review
ADAR RNA editing enzymes (denosine eminases acting on NA) that convert adenosine bases to inosines were first identified biochemically 30 years ago. Since then, studies on ADARs in genetic model organisms, and evolutionary comparisons between them, continue to reveal a surprising range of pleiotropic biological effects of ADARs. This review focuses on , which has a single gene encoding a homolog of vertebrate ADAR2 that site-specifically edits hundreds of transcripts to change individual codons in ion channel subunits and membrane and cytoskeletal proteins. ADAR is involved in the control of neuronal excitability and neurodegeneration and, intriguingly, in the control of neuronal plasticity and sleep. ADAR also interacts strongly with RNA interference, a key antiviral defense mechanism in invertebrates. Recent crystal structures of human ADAR2 deaminase domain-RNA complexes help to interpret available information on ADAR isoforms and on the evolution of ADARs from tRNA deaminase ADAT proteins. ADAR RNA editing is a paradigm for the now rapidly expanding range of RNA modifications in mRNAs and ncRNAs. Even with recent progress, much remains to be understood about these groundbreaking ADAR RNA modification systems.
Topics: Adenosine Deaminase; Animals; Drosophila Proteins; Drosophila melanogaster; Evolution, Molecular; Gene Expression; Humans; Isoenzymes; Nervous System; Protein Binding; Protein Interaction Domains and Motifs; RNA Editing; RNA Interference; RNA, Messenger; RNA-Binding Proteins; Structure-Activity Relationship; Substrate Specificity; Vertebrates
PubMed: 28559490
DOI: 10.1261/rna.060921.117 -
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 -
International Journal of Molecular... Apr 2017The evolution of cancer cells is believed to be dependent on genetic or epigenetic alterations. However, this concept has recently been challenged by another mode of... (Review)
Review
The evolution of cancer cells is believed to be dependent on genetic or epigenetic alterations. However, this concept has recently been challenged by another mode of nucleotide alteration, RNA editing, which is frequently up-regulated in cancer. RNA editing is a biochemical process in which either Adenosine or Cytosine is deaminated by a group of RNA editing enzymes including ADAR (Adenosine deaminase; RNA specific) or APOBEC3B (Apolipoprotein B mRNA Editing Enzyme Catalytic Subunit 3B). The result of RNA editing is usually adenosine to inosine (A-to-I) or cytidine to uridine (C-to-U) transition, which can affect protein coding, RNA stability, splicing and microRNA-target interactions. The functional impact of these alterations is largely unclear and is a subject of extensive research. In the present review, we will specifically focus on the influence of ADARs on carcinogenesis via the regulation of microRNA processing and functioning. This follows a brief review of the current knowledge of properties of ADAR enzyme, RNA editing, and microRNA processing.
Topics: Adenosine Deaminase; Animals; Feedback, Physiological; Gene Expression Regulation, Neoplastic; Humans; MicroRNAs; Models, Genetic; Neoplasms; RNA Editing; RNA-Binding Proteins
PubMed: 28398248
DOI: 10.3390/ijms18040799