Anthony J Sadler

Publications of Anthony J Sadler

• Dynamiting viruses with MxA.

  Authors: Anthony J Sadler, Bryan R G Williams

  Immunity. 10/2011; 35(4):491-3.

  The crystal structure of the interferon-induced member of the dynamin family MxA presented by Gao et al. (2011) in this issue of Immunity reveals the molecule's higher-order structure, therebyThe crystal structure of the interferon-induced member of the dynamin family MxA presented by Gao et al. (2011) in this issue of Immunity reveals the molecule's higher-order structure, thereby providing insight into the protein's antiviral action as a molecular machine.

• Orchestration of the activation of protein kinase R by the RNA-binding motif.

  Authors: Anthony J Sadler

  Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research. 04/2010; 30(4):195-204.

  The protein kinase R (PKR) constitutes part of the host antiviral response. PKR activation is regulated by the N-terminus of protein, which encodes tandem RNA-binding motifs (RBMs). The fullThe protein kinase R (PKR) constitutes part of the host antiviral response. PKR activation is regulated by the N-terminus of protein, which encodes tandem RNA-binding motifs (RBMs). The full capabilities of RBMs from PKR and other proteins have surpassed the narrow specificities initially determined as merely binding double-stranded RNA. Recognition of the increased affinity of the RBM for additional RNA species has established an immunological distinction by which PKR can detect exogenous RNAs, as well as identified PKR-mediated expression of specific endogenous genes. Furthermore, as RBMs also mediate interactions with other proteins, including PKR itself, this motif connects PKR to the broader RNA metabolism. Given the fundamental importance of protein-RNA interactions, not only in the innate immune response to intracellular pathogens, but also to coordinate the cellular replication machinery, there is considerable interest in the mechanisms by which proteins recognize and respond to RNA. This review appraises our understanding of how PKR activity is modulated by the RBMs.

• Modified vaccinia virus Ankara can activate NF-kappaB transcription factors through a double-stranded RNA-activated protein kinase (PKR)-dependent pathway during the early phase of virus replication.

  Authors: Heather E Lynch, Caroline A Ray, Katrina L Oie, Justin J Pollara, Ian T D Petty, Anthony J Sadler, Bryan R G Williams, David J Pickup

  Virology. 08/2009;

  Modified vaccinia virus Ankara (MVA), which is a promising replication-defective vaccine vector, is unusual among the orthopoxviruses in activating NF-kappaB transcription factors in cells of severalModified vaccinia virus Ankara (MVA), which is a promising replication-defective vaccine vector, is unusual among the orthopoxviruses in activating NF-kappaB transcription factors in cells of several types. In human embryonic kidney (HEK 293T) cells, the MVA-induced depletion of IkappaBalpha required to activate NF-kappaB is inhibited by UV-inactivation of the virus, and begins before viral DNA replication. In HEK 293T, CHO, or RK13 cells, expression of the cowpox virus CP77 early gene, or the vaccinia virus K1L early gene suppresses MVA-induced IkappaBalpha depletion. In mouse embryonic fibroblasts (MEFs), MVA induction of IkappaBalpha depletion is dependent on the expression of mouse or human double-stranded RNA-activated protein kinase (PKR). These results demonstrate that events during the early phase of MVA replication can induce PKR-mediated processes contributing both to the activation of NF-kappaB signaling, and to processes that may restrict viral replication. This property may contribute to the efficacy of this vaccine virus.

• Promyelocytic leukemia zinc finger protein regulates interferon-mediated innate immunity.

  Authors: Dakang Xu, Michelle Holko, Anthony J Sadler, Bernadette Scott, Shigeki Higashiyama, Windy Berkofsky-Fessler, Melanie J McConnell, Pier Paolo Pandolfi, Jonathan D Licht, Bryan R G Williams

  Immunity. 07/2009; 30(6):802-16.

  Interferons (IFNs) direct innate and acquired immune responses and, accordingly, are used therapeutically to treat a number of diseases, yet the diverse effects they elicit are not fully understood.Interferons (IFNs) direct innate and acquired immune responses and, accordingly, are used therapeutically to treat a number of diseases, yet the diverse effects they elicit are not fully understood. Here, we identified the promyelocytic leukemia zinc finger (PLZF) protein as a previously unrecognized component of the IFN response. IFN stimulated an association of PLZF with promyelocytic leukemia protein (PML) and histone deacetylase 1 (HDAC1) to induce a decisive subset of IFN-stimulated genes (ISGs). Consequently, PLZF-deficient mice had a specific ISG expression defect and as a result were more susceptible to viral infection. This susceptibility correlated with a marked decrease in the expression of the key antiviral mediators and an impaired IFN-mediated induction of natural killer cell function. These results provide new insights into the regulatory mechanisms of IFN signaling and the induction of innate antiviral immunity.

• An antiviral response directed by PKR phosphorylation of the RNA helicase A.

  Authors: Anthony J Sadler, Olivier Latchoumanin, David Hawkes, Johnson Mak, Bryan R G Williams

  PLoS pathogens. 03/2009; 5(2):e1000311.

  The double-stranded RNA-activated protein kinase R (PKR) is a key regulator of the innate immune response. Activation of PKR during viral infection culminates in phosphorylation of the alpha subunitThe double-stranded RNA-activated protein kinase R (PKR) is a key regulator of the innate immune response. Activation of PKR during viral infection culminates in phosphorylation of the alpha subunit of the eukaryotic translation initiation factor 2 (eIF2alpha) to inhibit protein translation. A broad range of regulatory functions has also been attributed to PKR. However, as few additional PKR substrates have been identified, the mechanisms remain unclear. Here, PKR is shown to interact with an essential RNA helicase, RHA. Moreover, RHA is identified as a substrate for PKR, with phosphorylation perturbing the association of the helicase with double-stranded RNA (dsRNA). Through this mechanism, PKR can modulate transcription, as revealed by its ability to prevent the capacity of RHA to catalyze transactivating response (TAR)-mediated type 1 human immunodeficiency virus (HIV-1) gene regulation. Consequently, HIV-1 virions packaged in cells also expressing the decoy RHA peptides subsequently had enhanced infectivity. The data demonstrate interplay between key components of dsRNA metabolism, both connecting RHA to an important component of innate immunity and delineating an unanticipated role for PKR in RNA metabolism.

• Protein kinase R-dependent regulation of interleukin-10 in response to double-stranded RNA.

  Authors: Arindam Chakrabarti, Anthony J Sadler, Niladri Kar, Howard A. Young, Robert H Silverman, Bryan R G Williams

  The Journal of biological chemistry. 08/2008;

  The double-stranded RNA-activated protein kinase R (PKR) is an important component of antiviral defense. PKR participates in different signaling pathways in response to various stimuli to regulateThe double-stranded RNA-activated protein kinase R (PKR) is an important component of antiviral defense. PKR participates in different signaling pathways in response to various stimuli to regulate translation via phosphorylation of the eukaryotic initiation factor 2alpha, and transcription via activating NF-kappaB and IRF-1, to induce pro-inflammatory cytokines. Here we show PKR regulates interleukin-10 induction in response to double-stranded RNA, bacterial lipopolysaccaride, and Sendai virus infection. Using chemical inhibitors, dominant negative constructs, and genetic knockouts, we demonstrate that the PKR-mediated interleukin-10 induction engages JNK and NF-kappaB. Together, our data demonstrate the role of PKR in regulating an anti-inflammatory cytokine. The findings have significance in antiviral, as well as broader innate immune responses.

• Interferon-inducible antiviral effectors.

  Authors: Anthony J Sadler, Bryan R G Williams

  Nature reviews. Immunology. 08/2008; 8(7):559-68.

  Since the discovery of interferons (IFNs), considerable progress has been made in describing the nature of the cytokines themselves, the signalling components that direct the cell response and theirSince the discovery of interferons (IFNs), considerable progress has been made in describing the nature of the cytokines themselves, the signalling components that direct the cell response and their antiviral activities. Gene targeting studies have distinguished four main effector pathways of the IFN-mediated antiviral response: the Mx GTPase pathway, the 2',5'-oligoadenylate-synthetase-directed ribonuclease L pathway, the protein kinase R pathway and the ISG15 ubiquitin-like pathway. As discussed in this Review, these effector pathways individually block viral transcription, degrade viral RNA, inhibit translation and modify protein function to control all steps of viral replication. Ongoing research continues to expose additional activities for these effector proteins and has revealed unanticipated functions of the antiviral response.

• Fine-tuning of the innate immune response by microRNAs.

  Authors: Michael P Gantier, Anthony J Sadler, Bryan R G Williams

  Immunology and cell biology. 85(6):458-62.

  MicroRNAs (miRNAs) are emerging as potent regulators of many biological processes, including cellular differentiation and disease. Recently, miRNA has been directly involved in innate immunity andMicroRNAs (miRNAs) are emerging as potent regulators of many biological processes, including cellular differentiation and disease. Recently, miRNA has been directly involved in innate immunity and transduction signalling by Toll-like receptors and the ensuing cytokine response. In this review, we present an overview of what is currently known of the involvement of miRNA and RNA interference components in the fine-tuning of innate immune responses.

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