Enhancement of Replication of RNA Viruses by ADAR1 via RNA Editing and Inhibition of RNA-Activated Protein Kinase

Gélinas, Jean-François; Clerzius, Guerline; Shaw, Eileen; Gatignol, Anne

doi:10.1128/jvi.00240-11

Cited by 88 publications

(92 citation statements)

References 94 publications

(170 reference statements)

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“…ADAR1, an A-to-I dsRNA editing enzyme, deaminates adenosine in dsRNA structures, thereby destabilizing dsRNA because I·U base pairs are less stable than A·U pairs (38,47). ADAR1 is known to compete with and suppress PKR activity (38,48). Thus, generation of dsRNA is not restricted to the C KO virus but also appears in parental virus-infected ADAR1 kd cells.…”

Section: Discussionmentioning

confidence: 99%

Measles Virus C Protein Impairs Production of Defective Copyback Double-Stranded Viral RNA and Activation of Protein Kinase R

Pfaller

Radeke

Cattaneo

et al. 2014

J Virol

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Measles virus (MV) lacking expression of C protein (C KO ) is a potent activator of the double-stranded RNA (dsRNA)-dependent protein kinase (PKR), whereas the isogenic parental virus expressing C protein is not. Here, we demonstrate that significant amounts of dsRNA accumulate during C KO mutant infection but not following parental virus infection. dsRNA accumulated during late stages of infection and localized with virus replication sites containing N and P proteins. PKR autophosphorylation and stress granule formation correlated with the timing of dsRNA appearance. Phospho-PKR localized to dsRNA-containing structures as revealed by immunofluorescence. Production of dsRNA was sensitive to cycloheximide but resistant to actinomycin D, suggesting that dsRNA is a viral product. Quantitative PCR (qPCR) analyses revealed reduced viral RNA synthesis and a steepened transcription gradient in C KO virus-infected cells compared to those in parental virus-infected cells. The observed alterations were further reflected in lower viral protein expression levels and reduced C KO virus infectious yield. RNA deep sequencing confirmed the viral RNA expression profile differences seen by qPCR between C KO mutant and parental viruses. After one subsequent passage of the C KO virus, defective interfering RNA (DI-RNA) with a duplex structure was obtained that was not seen with the parental virus. We conclude that in the absence of C protein, the amount of PKR activator RNA, including DI-RNA, is increased, thereby triggering innate immune responses leading to impaired MV growth.

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Section: Discussionmentioning

confidence: 99%

Measles Virus C Protein Impairs Production of Defective Copyback Double-Stranded Viral RNA and Activation of Protein Kinase R

Pfaller

Radeke

Cattaneo

et al. 2014

J Virol

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“…The proviral and antiapoptotic activities of ADAR1 have been demonstrated with several viruses, including measles virus, hepatitis delta virus, Venezuelan equine encephalitis virus, yellow fever virus, and HIV (27,31,40,41). ADAR1 deficiency, as illustrated with measles virus, correlates with increased PKR activation (24), increased IFN␤ induction (25), increased SG responses (7), and increased cytotoxicity and apoptosis (25,42).…”

mentioning

confidence: 99%

Editing of Cellular Self-RNAs by Adenosine Deaminase ADAR1 Suppresses Innate Immune Stress Responses

George

Ramaswami

et al. 2016

Journal of Biological Chemistry

125

106

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One mechanism by which cells respond to different forms of stress is the global reduction of protein synthesis (1). Phosphorylation of protein synthesis initiation factor eIF2␣ on serine 51 is recognized as a universal mechanism of translation suppression in response to cellular stress (1, 2). Four different protein kinases are activated in mammalian cells in response to different stresses, and they all catalyze Ser-51 phosphorylation of eIF2␣ as follows: protein kinase regulated by RNA (PKR) activated by double-stranded RNA; heme-regulated inhibitor kinase activated by hemin deficiency and oxidative stress; general control non-derepressible kinase 2 (GCN2) activated by amino acid deficiency; and PKR-like endoplasmic reticulum kinase activated by protein misfolding and endoplasmic reticulum stress (2, 3). The global inhibition of translation in cultured cells mediated by eIF2␣ phosphorylation is linked to the formation of stress granules (SG), 2 cytoplasmic aggregates of stalled 40S ribosomal subunit-containing translation initiation complexes, translation initiation factors, and RNA-binding proteins, including Ras GTPase-activating protein-Src homology 3 domain binding protein 1 G3BP1 (4). Stress granule formation is one hallmark of virus infection, serving as an index of innate immune responses, and is PKR-dependent for a variety of viruses (5-8).A cornerstone of innate antiviral immunity is the interferon (IFN) system (9, 10). IFNs act through the transcriptional induction of IFN-stimulated genes that encode products responsible for the biological activities of IFNs, including the ability of IFNs to inhibit virus multiplication and enhance apoptosis (11-13). Among the IFN-stimulated gene products is the PKR kinase induced by IFN through canonical JAK-STAT signaling (14 -16). PKR is activated by binding dsRNA that mediates PKR dimerization and autophosphorylation; activated PKR catalyzes the phosphorylation of eIF2␣ (17)(18)(19)(20). In the case of several viruses, PKR displays antiviral and proapoptotic activities (12,21,22). Exemplified by measles virus, PKR sufficiency and kinase activation correlate with reduced virus growth (23, 24), enhanced induction of IFN␤ (25,26), increased SG responses (7), and increased cytotoxicity and apoptosis (27,28). The central importance of PKR furthermore is illustrated both by the large number of viruses that encode gene products that antagonize PKR activation and function, and by the effects of genetic disruption of the Pkr gene (12,13,29).Similar to PKR, ADAR1 (adenosine deaminase acting on RNA1) is an IFN-inducible dsRNA-binding protein with enzyme activity (30, 31). However, unlike PKR, ADAR1 uses dsRNA as a substrate (32). ADAR1 catalyzes the C6 deamination of adenosine (A) in dsRNA structures to generate inosine (I), a process known as A-to-I editing (33,34) samuel@lifesci.ucsb.edu.2 The abbreviations used are: SG, stress granule; ADAR1, adenosine deaminase acting on RNA1; MEF, mouse embryo fibroblast; mmPCR-seq, microfluidics-based multiplex PCR and deep sequencing;...

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“…There are two protein size forms of ADAR1 (P110 and P150). ADAR1-P110 is constitutively expressed in ubiquitous types of cells, whereas P150 is only expressed when cells are stimulated by some activators (20,21). The adenosine-to-inosine editing is of broad physiological function.…”

mentioning

confidence: 99%

“…Despite the complexity, ADAR1 has been shown to promote the infection of numerous types of viruses, including VSV; measles virus; EBV; influenza virus; dengue virus; HIV, type 1; human respiratory syncytial virus; and human herpesviruses 8 (20,21). An increasing number of studies have demonstrated that ADAR1-mediated enhancement of viral infections is mainly through RNA editing or inhibition of IFN activity (including both IFN-I production and IFN-activated PKR antiviral activity) (21).…”

mentioning

confidence: 99%

Ubiquitin-dependent Turnover of Adenosine Deaminase Acting on RNA 1 (ADAR1) Is Required for Efficient Antiviral Activity of Type I Interferon

Qian

Zuo

et al. 2016

Journal of Biological Chemistry

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Edited by George DeMartinoAdenosine deaminase acting on RNA 1 (ADAR1) catalyzes RNA editing of cellular and viral RNAs. Besides RNA editing, ADAR1 has recently been shown to play important roles in maintaining the body balance, including tissue homoeostasis, organ development, and autoimmune regulations, by inhibiting both IFN production and subsequent IFN-activated pathways. Accordingly, the question was raised how IFN signaling induced by viral infections overcomes the inhibitory effect of constitutively expressed ADAR1 (ADAR1-P110) to execute efficient antiviral activity. Here we unexpectedly found that IFN signaling promoted Lys 48 -linked ubiquitination and degradation of ADAR1-P110. Furthermore, we identified the E3 ligase ␤ transducin repeat-containing protein responsible for IFN-mediated ADAR1-P110 down-regulation. IFN signaling promoted the interaction between ␤ transducin repeat-containing protein and ADAR1-P110 as well as protein turnover of ADAR1-P110. Moreover, we found that both lysine 574 and 576 are essential for ADAR1-P110 ubiquitination. Critically, we demonstrated that down-regulation of ADAR1-P110 is required for IFN signaling to execute efficient antiviral activity during viral infections. These findings renew the understanding of the mechanisms by which IFN signaling acts to achieve antiviral functions and may provide potential targets for IFN-based antiviral therapy.

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Enhancement of Replication of RNA Viruses by ADAR1 via RNA Editing and Inhibition of RNA-Activated Protein Kinase

Cited by 88 publications

References 94 publications

Measles Virus C Protein Impairs Production of Defective Copyback Double-Stranded Viral RNA and Activation of Protein Kinase R

Measles Virus C Protein Impairs Production of Defective Copyback Double-Stranded Viral RNA and Activation of Protein Kinase R

Editing of Cellular Self-RNAs by Adenosine Deaminase ADAR1 Suppresses Innate Immune Stress Responses

Ubiquitin-dependent Turnover of Adenosine Deaminase Acting on RNA 1 (ADAR1) Is Required for Efficient Antiviral Activity of Type I Interferon

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