33 research outputs found
The regulation of type I interferon production by paramyxoviruses
No full textResearch supported by The Wellcome Trust (087751/A/08/Z)Experimentally, paramyxoviruses are conventionally considered good inducers of type I interferons (IFN-alpha/beta), and have been used as agents in the commercial production of human IFN-alpha. However, in the last few years it has become clear that viruses in general mount a major challenge to the IFN system, and paramyxoviruses are no exception. Indeed, most paramyxoviruses encode mechanisms to inhibit both the production of, and response to, type I IFN. Here we review our knowledge of the type I IFN-inducing signals (by so-called pathogen-associated molecular patterns, or PAMPs) produced during paramyxovirus infections, and discuss how paramyxoviruses limit the production of PAMPs and inhibit the cellular responses to PAMPs by interfering with the activities of the pattern recognition receptors (PRRs), mda-5, and RIG-I, as well as downstream components in the type I IFN induction cascades.Peer reviewe
Paramyxovirus V proteins interact with the RNA helicase LGP2 to inhibit RIG-I-dependent interferon induction
No full textThis work was supported by the Wellcome Trust (grant AL087751/B)RIG-I and mda-5 are activated by viral RNA and stimulate type I interferon production. Laboratory of genetics and physiology 2 (LGP2) shares homology with RIG-I and mda-5 but lacks the CARD domains required for signaling. The V proteins of paramyxoviruses limit interferon induction by binding mda-5 and preventing its activation; however, they do not bind RIG-I and have not been considered inhibitors of RIG-I signaling. Here we uncover a novel mechanism of RIG-I inhibition in which the V protein of parainfluenzavirus type 5 (PIV5; formerly known as simian virus type 5 [SV5]) interacts with LGP2 and cooperatively inhibits induction by RIG-I ligands. A complex between RIG-I and LGP2 is observed in the presence of PIV5-V, and we propose that this complex is refractory to activation by RIG-I ligands. The V proteins from other paramyxoviruses also bind LGP2 and demonstrate LGP2-dependent inhibition of RIG-I signaling. This is significant, because it demonstrates a general mechanism for the targeting of the RIG-I pathway by paramyxoviruses.Peer reviewe
LGP2 plays a critical role in sensitizing mda-5 to activation by double-stranded RNA.
No full textThe DExD/H box RNA helicases retinoic acid-inducible gene-I (RIG-I) and melanoma differentiation associated gene-5 (mda-5) sense viral RNA in the cytoplasm of infected cells and activate signal transduction pathways that trigger the production of type I interferons (IFNs). Laboratory of genetics and physiology 2 (LGP2) is thought to influence IFN production by regulating the activity of RIG-I and mda-5, although its mechanism of action is not known and its function is controversial. Here we show that expression of LGP2 potentiates IFN induction by polyinosinic-polycytidylic acid [poly(I:C)], commonly used as a synthetic mimic of viral dsRNA, and that this is particularly significant at limited levels of the inducer. The observed enhancement is mediated through co-operation with mda-5, which depends upon LGP2 for maximal activation in response to poly(I:C). This co-operation is dependent upon dsRNA binding by LGP2, and the presence of helicase domain IV, both of which are required for LGP2 to interact with mda-5. In contrast, although RIG-I can also be activated by poly(I:C), LGP2 does not have the ability to enhance IFN induction by RIG-I, and instead acts as an inhibitor of RIG-I-dependent poly(I:C) signaling. Thus the level of LGP2 expression is a critical factor in determining the cellular sensitivity to induction by dsRNA, and this may be important for rapid activation of the IFN response at early times post-infection when the levels of inducer are low
Interferons and viruses: an interplay between induction, signalling, antiviral responses and virus countermeasures
No full textThe interferon (IFN) system is an extremely powerful antiviral response that is capable of controlling most, if not all, virus infections in the absence of adaptive immunity. However, viruses can still replicate and cause disease in vivo, because they have some strategy for at least partially circumventing the IFN response. We reviewed this topic in 2000 [Goodbourn, S., Didcock, L. & Randall, R. E. (2000). J Gen Virol 81, 2341-2364] but, since then, a great deal has been discovered about the molecular mechanisms of the IFN response and how different viruses circumvent it. This information is of fundamental interest, but may also have practical application in the design and manufacture of attenuated virus vaccines and the development of novel antiviral drugs. In the first part of this review, we describe how viruses activate the IFN system, how IFNs induce transcription of their target genes and the mechanism of action of IFN-induced proteins with antiviral action. In the second part, we describe how viruses circumvent the IFN response. Here, we reflect upon possible consequences for both the virus and host of the different strategies that viruses have evolved and discuss whether certain viruses have exploited the IFN response to modulate their life cycle (e.g. to establish and maintain persistent/latent infections), whether perturbation of the IFN response by persistent infections can lead to chronic disease, and the importance of the IFN system as a species barrier to virus infections. Lastly, we briefly describe applied aspects that arise from an increase in our knowledge in this area, including vaccine design and manufacture, the development of novel antiviral drugs and the use of IFN-sensitive oncolytic viruses in the treatment of cancer.</p
Signal transduction and nuclear targeting: regulation of transcription factor activity by subcellular localisation
No full textHuman β-interferon gene expression is regulated by an inducible enhancer element
No full textWe have localized the regulatory sequence required for viral or poly([)-poly(C) activation of human β-interferon gene expression to a region located between −37 and −77 from the mRNA cap site. This sequence has the characteristics of an inducible enhancer element: it can act upstream or downstream of the β-interferon gene regardless of its orientation, and at distances up to approximately 1 kilobase from its normal location. Moreover, this element can confer inducibility on a heterologous promoter. Further analysis has identified a minimal regulatory element of 14 base pairs within this enhancer. Sequences closely related to this element are present five times within the 5′-flanking regions of both the α- and β-interferon genes. The number of these minimal regulatory elements required for maximal β-interferon gene expression appears to differ in different cell lines
Regulation of transcription of the Aedes albopictus cecropin A1 gene: a role for p38 mitogen-activated protein kinase
No full textRegulation of the Aedes albopictus cecropin A1 promoter was studied to provide insight into the transcriptional control of this antimicrobial peptide (AMP) gene in mosquitoes. Gene expression levels of cecropin A1 increased in A. albopictus C6/36 cells in response to heat killed Escherichiacoli. Reporter gene assays incorporating -757 to +32 of the A. albopictus cecropin A1 promoter revealed that E. coli could induce expression in these cells with more pronounced expression than that seen with lipopolysaccharide (LPS). Analysis of deletion constructs demonstrated that the 5' boundary of the regulatory region for the activation of this AMP was located between -173 and -64. Western blotting with anti-phospho-specific antibodies demonstrated that p38 mitogen-activated protein kinase (p38 MAPK) and c-Jun N-terminal kinase (JNK) were activated by LPS, whereas only p38 MAPK was activated by E. coli. Moreover, pharmacological experiments revealed that pre-incubation of cells with the p38 MAPK inhibitor SB203580 resulted in a striking activation of the cecropin A1 promoter following immune challenge, demonstrating that p38 MAPK negatively regulates cecropin A1 promoter activity. Finally the region required for the negative regulation by p38 MAPK was identified as being between -173 and -64. This report is the first to show involvement of the p38 MAPK pathway in the negative regulation of AMP production in a mosquito
