Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.5.4.4 (adenosine deaminase)
 5,136 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Members of the ADAR (adenosine deaminase that acts on RNA) enzyme family catalyze the hydrolytic deamination of adenosine to inosine within double-stranded RNAs, a poorly understood process that is critical to mammalian development. We have performed fluorescence resonance energy transfer experiments in mammalian cells transfected with fluorophore-bearing ADAR1 and ADAR2 fusion proteins to investigate the relationship between these proteins. These studies conclusively demonstrate the homodimerization of ADAR1 and ADAR2 and also show that ADAR1 and ADAR2 form heterodimers in human cells. RNase treatment of cells expressing these fusion proteins changes their localization but does not affect dimerization. Taken together these results suggest that homo- and heterodimerization are important for the activity of ADAR family members in vivo and that these associations are RNA independent.
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PMID:FRET analysis of in vivo dimerization by RNA-editing enzymes. 1661 4

The interferon-inducible adenosine deaminase that acts on double-stranded RNA (ADAR1-L) has been proposed to be one of the antiviral effector proteins within the complex innate immune response. Here, the potential role of ADAR1-L in the innate immune response to lymphocytic choriomeningitis virus (LCMV), a widely used virus model, was studied. Infection with LCMV clearly upregulated ADAR1-L expression and activity. The editing activity of ADAR1-L on an RNA substrate was not inhibited by LCMV replication. Accordingly, an adenosine-to-guanosine (A-to-G) and uracil-to-cytidine (U-to-C) hypermutation pattern was found in the LCMV genomic RNA in infected cell lines and in mice. In addition, two hypermutated clones with a high level of A-to-G or U-to-C mutations within a short stretch of the viral genome were isolated. Analysis of the functionality of viral glycoprotein revealed that A-to-G- and U-to-C-mutated LCMV genomes coded for nonfunctional glycoprotein at a surprisingly high frequency. Approximately half the GP clones with an amino acid mutation lacked functionality. These results suggest that ADAR1-L-induced mutations in the viral RNA lead to a loss of viral protein function and reduced viral infectivity. This study therefore provides strong support for the contribution of ADAR1-L to the innate antiviral immune response.
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PMID:A-to-G hypermutation in the genome of lymphocytic choriomeningitis virus. 1702 Sep 43

Adenosine to inosine (A-to-I) modification by the ADAR (adenosine deaminase that acts on RNA) enzymes perform the most common type of RNA editing in metazoans. ADARs use double stranded RNA as substrates but allow interruptions of bulges and loops in the structure. It is well known that these enzymes can use messenger RNA as targets for A-to-I editing and thereby recode the transcript. Both ADAR1 and ADAR2 have been proven to be able to also target short double stranded RNA molecules of the same size as a microRNA. However, it is not until recently shown that A-to-I editing occurs in microRNAs and its precursors. Since the editing activity is found both in the nucleus and the cytoplasm there are several steps during the microRNA maturation pathway that can be targeted for modification. This review will give an overview of what is known today about the interactions between the endogenous RNA interference process and RNA editing. It will also give some insight into the power of A-to-I modification in its ability to increase the variety of microRNA gene silencing.
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PMID:A-to-I editing challenger or ally to the microRNA process. 1762 90

We and other investigators have demonstrated up-regulation of the expression of the RNA-editing gene 150-kDa adenosine deaminase that acts on RNA (ADAR1) in systemic lupus erythematosus (SLE) T cells and B cells, peripheral blood mononuclear cells (PBMC), natural killer (NK) cells. The presence of a small proportion of activated T cells is the hallmark of SLE. Therefore, it was hypothesized that 150-kDa ADAR1 gene expression is induced by the physiological activation of T cells. To examine this hypothesis, normal T cells were activated by anti-CD3-epsilon plus anti-CD28 for various time periods from 0 to 48 hr. The expression of 110-kDa and 150-kDa ADAR1, and interleukin (IL)-2 and beta-actin gene transcripts was analysed. An approximately fourfold increase in 150-kDa ADAR1 gene expression was observed in activated T cells. ADAR2 gene transcripts are substrates for ADAR1 and ADAR2 enzymes. Therefore, we assessed the role of the 150-kDa ADAR enzyme in editing of ADAR2 gene transcripts. In activated T cells, site-selective editing of the -2 site was observed. Previous studies indicate that this site is predominantly edited by ADAR1. In addition to this, novel editing sites at base positions -56, -48, -45, -28, -19, -15, +46 and +69 were identified in activated T cells. On the basis of these results, it is proposed that 150-kDa ADAR1 gene expression is selectively induced in T cells by anti-CD3-epsilon and anti-CD28 stimulation and that it may play a role in site-selective editing of gene transcripts and in altering the functions of several gene products of T cells during activation and proliferation.
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PMID:Induction of 150-kDa adenosine deaminase that acts on RNA (ADAR)-1 gene expression in normal T lymphocytes by anti-CD3-epsilon and anti-CD28. 1789 25

Previous studies showed adenosine deaminase that acts on RNA (ADAR1) up-regulated in alveolar macrophages (AMs) by LPS treatment, whereas its roles in acute lung injury (ALI) are still unclear. Here, we report that up-regulation of inducible ADAR1 p150 isoform in macrophages stimulated with LPS and in AMs harvested from an ALI rat model. Knockdown of ADAR1 p150 by small interfering RNA in AMs suppressed macrophage inflammatory protein 1 (MIP-1) secretion while enhancing that of IL-10 compared with those control cells upon LPS stimulation. To further confirm the role of p150 in AMs, adoptive transfer of LPS-activated NR8383 cells was performed in healthy rats, and severity of inflammatory response was assessed by investigating cellular pattern in bronchoalveolar lavage fluid and calculating alveolar-arterial oxygen difference [D(A-a)O2]. Acute lung injury was induced by LPS-activated NR8383 cells with either normal or lower ADAR1 expression levels, and ALI in rats and the lung inflammation was attenuated significantly by knockdown ADAR1 p150 in transferred cells both in polymorphonuclear leukocyte infiltration and D(A-a)O2. The roles of MIP-1 and IL-10 in the development of ALI were also tested in animals receiving neutralizing antibodies. Administration of anti-MIP-1 inhibited lung polymorphonuclear leukocytes infiltration and lung damage, as well as D(A-a)O2, whereas anti-IL-10 reversed the protection effects. In conclusion, ADAR1 p150 is functionally significant in the development of ALI. It likely exerts its effects in part by mediating the expression of proinflammatory and anti-inflammatory cytokines and influencing tissue neutrophil recruitment and D(A-a)O2. It also implied that ADAR1 inhibitors may help attenuate local inflammatory lung damage.
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PMID:Adenosine deaminase that acts on RNA 1 p150 in alveolar macrophage is involved in LPS-induced lung injury. 1852 Jul 2

The p150 form of the RNA-specific adenosine deaminase ADAR1 is interferon-inducible and catalyzes A-to-I editing of viral and cellular RNAs. We have characterized mouse genomic clones containing the promoter regions required for Adar1 gene transcription and analyzed interferon induction of the p150 protein using mutant mouse cell lines. Transient transfection analyses using reporter constructs led to the identification of three promoters, one interferon-inducible (P(A)) and two constitutively active (P(B) and P(C)). The TATA-less P(A) promoter, characterized by the presence of a consensus ISRE element and a PKR kinase KCS-like element, directed interferon-inducible reporter expression in rodent and human cells. Interferon induction of p150 was impaired in mouse cells deficient in IFNAR receptor, JAK1 kinase or STAT2 but not STAT1. Whereas Adar1 gene organization involving multiple promoters and alternative exon 1 structures was highly preserved, sequences of the promoters and exon 1 structures were not well conserved between human and mouse.
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PMID:Organization of the mouse RNA-specific adenosine deaminase Adar1 gene 5'-region and demonstration of STAT1-independent, STAT2-dependent transcriptional activation by interferon. 1877 82

Adenosine deaminases acting on RNA (ADARs) convert adenosines to inosines in double-stranded RNA in animals. Identification of more ADAR targets and genome sequences of diverse eukaryotes present an opportunity to elucidate the origin and evolution of ADAR-mediated RNA editing. Comparative analysis of the adenosine deaminase family indicates that the first ADAR might have evolved from adenosine deaminases acting on tRNAs after the split of protozoa and metazoa. ADAR1 and ADAR2 arose by gene duplications in early metazoan evolution, approximately 700 million years ago, while ADAR3 and TENR might originate after Urochordata-Vertebrata divergence. More ADAR or ADAR-like genes emerged in some animals (e.g., fish). Considering the constrained structure, ADAR targets are proposed to have evolved from transposable elements and repeats, random selection, and fixation, and intermolecular pairs of sense and antisense RNA. In some degree, increased ADAR-mediated gene regulation should substantially contribute to the emergence and evolution of complex metazoans, particularly the nervous system.
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PMID:Origins and evolution of ADAR-mediated RNA editing. 1947 81

The interferon-induced protein kinase RNA activated (PKR) is activated after virus infection. This activation is transient during the human immunodeficiency virus type 1 (HIV-1) infection of lymphocytes, and the protein is not activated at the peak of infection. We observed that interferon-induced adenosine deaminase acting on RNA 1-p150 (ADAR1-p150) and ADAR1-p110 expression increases while the virus replicates actively. Furthermore, both forms of ADAR1 show enhanced interactions with PKR at the peak of HIV infection, suggesting a role for this protein in the regulation of PKR activation. We observed that ADAR1-p150, as previously shown for the TAR RNA binding protein (TRBP), reverses the PKR inhibition of HIV expression and production in HEK 293T cells. This activity requires the Z-DNA binding motif and the three double-stranded RNA binding domains but not the catalytic domain. In astrocytic cells, ADAR1-p150 increased HIV expression and production to an extent similar to that of TRBP. Small interfering RNAs against ADAR1-p150 moderately decreased HIV production. These results indicate that two interferon-induced proteins, ADAR1 and PKR, have antagonistic functions on HIV production. They suggest that ADAR1 and TRBP belong to a multiprotein complex that inhibits PKR during the HIV infection of lymphocytes.
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PMID:ADAR1 interacts with PKR during human immunodeficiency virus infection of lymphocytes and contributes to viral replication. 1960 74

ADAR1 (adenosine deaminase acting on RNA) catalyzes the conversion of adenosine to inosine, a process known as A-to-I editing. Extensive A-to-I editing has been described in viral RNAs isolated from the brains of patients persistently infected with measles virus, although the precise role of ADAR during measles virus infection remains unknown. We generated human HeLa cells stably deficient in ADAR1 ("ADAR1(kd) cells") through short hairpin RNA-mediated knockdown, and using these cells, we tested the effect of ADAR1 deficiency on measles virus (MVvac strain) growth and virus-induced cell death. We found that the growth of mutant viruses lacking expression of the viral accessory proteins V and C (V(ko) and C(ko), respectively) was decreased in ADAR1-deficient cells compared with ADAR1-sufficient cells. In addition, apoptosis was enhanced in ADAR1-deficient cells following infection with wild type and V(ko) virus but not following infection with C(ko) virus or treatment with tumor necrosis factor-alpha or staurosporine. Furthermore, in C(ko)-infected ADAR1-sufficient cells when ADAR1 did not protect against apoptosis, caspase cleavage of the ADAR1 p150 protein was detected. Finally, enhanced apoptosis in ADAR1(kd) cells following infection with wild type and V(ko) virus correlated with enhanced activation of PKR kinase and interferon regulatory factor IRF-3. Taken together, these results demonstrate that ADAR1 is a proviral, antiapoptotic host factor in the context of measles virus infection and suggest that the antiapoptotic activity of ADAR1 is achieved through suppression of activation of proapoptotic and double-stranded RNA-dependent activities, as exemplified by PKR and IRF-3.
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PMID:RNA-specific adenosine deaminase ADAR1 suppresses measles virus-induced apoptosis and activation of protein kinase PKR. 1971 21

The protein kinase regulated by RNA (PKR) and the adenosine deaminase acting on RNA (ADAR1) are interferon-inducible enzymes that play important roles in biologic processes including the antiviral actions of interferons, signal transduction, and apoptosis. PKR catalyzes the RNA-dependent phosphorylation of protein synthesis initiation factor eIF-2 alpha, thereby leading to altered translational patterns in interferon-treated and virus-infected cells. PKR also modulates signal transduction responses, including the induction of interferon. ADAR1 catalyzes the deamination of adenosine (A) to generate inosine (I) in RNAs with double-stranded character. Because I is recognized as G instead of A, A-to-I editing by ADAR1 can lead to genetic recoding and altered RNA structures. The importance of PKR and ADAR1 in innate antiviral immunity is illustrated by a number of viruses that encode either RNA or protein viral gene products that antagonize PKR and ADAR1 enzymatic activity, localization, or stability.
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PMID:Tipping the balance: antagonism of PKR kinase and ADAR1 deaminase functions by virus gene products. 1971 57


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