Adenosine Deaminase Acting on RNA 1 (ADAR1) Suppresses the Induction of Interferon by Measles Virus

Li, Zhiqun; Okonski, Kristina M.; Samuel, Charles E.

doi:10.1128/jvi.06307-11

Cited by 59 publications

(83 citation statements)

References 63 publications

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“…Short structured RNAs without a 5Ј-triphosphate are known to be weak inducers of IFN-␤ (42), but they still activate PKR (24,37), suggesting that PKR activation is not sufficient for IFN-␤ induction. Although the activation of IRF3 is PKR-independent in both RNA transfected and measles virus infected HeLa cells, the activation of NF-B is enhanced by PKR (27,43).…”

Section: Discussionmentioning

confidence: 98%

“…PKR has emerged as an important modulator of IFN-␤ gene induction following infection with RNA viruses, including negative-stranded (27,43), positive-stranded (49 -53) and doublestranded (54) RNA viruses. But, the molecular mechanism by which PKR affects IFN-␤ induction largely remains unresolved.…”

Section: Discussionmentioning

confidence: 99%

“…Impaired IFN-␤ transcript induction in HeLa cells stably knocked down for PKR is known following dsRNA transfection (24) or measles virus infection (27,43). Using a transient knockdown strategy we earlier had established that, in addition to PKR, the IPS-1 adaptor protein for the RLR cytosolic signaling pathway was required for maximal IFN-␤ induction by measles ko virus, and at 24 h after infection extracts were prepared and western immunoblot analyses performed using antibodies against IB-␣, MV H protein and eIF-2␣, and ␣-tubulin as a loading control.…”

Section: Discussionmentioning

confidence: 99%

“…Because NF-B is one of the transcription factors required for IFN-␤ induction and the activation of NF-B and induction of IFN-␤ are enhanced by PKR in measles virus-infected and RNA-transfected cells (24,27,43) we hypothesized that differential NF-B signaling may be responsible in part for the differences in IFN-␤ expression triggered by the different-sized dsRNAs. We previously observed that the inhibitor of NF-B signaling, IB-␣, was degraded following Pds50 and pIpC transfection (24).…”

Section: Dsrna Length-dependent Induction Of Ifn-␤ and Pkr-dependent mentioning

confidence: 99%

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Protein Kinase PKR Amplification of Interferon β Induction Occurs through Initiation Factor eIF-2α-mediated Translational Control

McAllister

Taghavi

Samuel

2012

Journal of Biological Chemistry

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Background: RNA-dependent protein kinase PKR regulates interferon induction. Results: Knockdown of PKR or mutation of initiation factor eIF-2␣ results in increased IB-␣ protein levels and decreased IFN-␤ induction in RNA-transfected and virus-infected cells. Conclusion: PKR amplifies IFN-␤ induction through an eIF-2␣ translational control response. Significance: PKR functions together with additional RNA sensors to modulate signaling leading to interferon gene induction.

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Dsrna Length-dependent Induction Of Ifn-␤ and Pkr-dependent mentioning

confidence: 99%

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Protein Kinase PKR Amplification of Interferon β Induction Occurs through Initiation Factor eIF-2α-mediated Translational Control

McAllister

Taghavi

Samuel

2012

Journal of Biological Chemistry

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“…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).…”

Section: G3bp1 (4) Stress Granule Formation Is One Hallmark Of Virusmentioning

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

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125

105

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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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ADAR1, inosine and the immune sensing system: distinguishing self from non‐self

2015

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The conversion of genomically encoded adenosine to inosine in dsRNA is termed as A-to-I RNA editing. This process is catalyzed by two of the three mammalian ADAR proteins (ADAR1 and ADAR2) both of which have essential functions for normal organismal homeostasis. The phenotype of ADAR2 deficiency can be primarily ascribed to a lack of site-selective editing of a single transcript in the brain. In contrast, the biology and substrates responsible for the Adar1(-/-) phenotype have remained more elusive. Several recent studies have identified that a feature of absence or reductions of ADAR1 activity, conserved across human and mouse models, is a profound activation of interferon-stimulated gene signatures and innate immune responses. Further analysis of this observation has lead to the conclusion that editing by ADAR1 is required to prevent activation of the cytosolic innate immune system, primarily focused on the dsRNA sensor MDA5 and leading to downstream signaling via MAVS. The delineation of this mechanism places ADAR1 at the interface between the cells ability to differentiate self- from non-self dsRNA. Based on MDA5 dsRNA recognition requisites, the mechanism indicates that the type of dsRNA must fulfil a particular structural characteristic, rather than a sequence-specific requirement. While additional studies are required to molecularly verify the genetic model, the observations to date collectively identify A-to-I editing by ADAR1 as a key modifier of the cellular response to endogenous dsRNA.

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Adenosine Deaminase Acting on RNA 1 (ADAR1) Suppresses the Induction of Interferon by Measles Virus

Cited by 59 publications

References 63 publications

Protein Kinase PKR Amplification of Interferon β Induction Occurs through Initiation Factor eIF-2α-mediated Translational Control

Protein Kinase PKR Amplification of Interferon β Induction Occurs through Initiation Factor eIF-2α-mediated Translational Control

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

ADAR1, inosine and the immune sensing system: distinguishing self from non‐self

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