IRF3

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Nicolas Ruggli - One of the best experts on this subject based on the ideXlab platform.

  • classical swine fever virus npro interacts with interferon regulatory factor 3 and induces its proteasomal degradation
    Journal of Virology, 2007
    Co-Authors: Oliver Bauhofer, Jon Duri Tratschin, Artur Summerfield, Martin A. Hofmann, Yoshihiro Sakoda, Nicolas Ruggli
    Abstract:

    Viruses have evolved a multitude of strategies to subvert the innate immune system by interfering with components of the alpha/beta interferon (IFN-alpha/beta) induction and signaling pathway. It is well established that the pestiviruses prevent IFN-alpha/beta induction in their primary target cells, such as epitheloidal and endothelial cells, macrophages, and conventional dendritic cells, a phenotype mediated by the viral protein N(pro). Central players in the IFN-alpha/beta induction cascade are interferon regulatory factor 3 (IRF3) and IRF7. Recently, it was proposed that classical swine fever virus (CSFV), the porcine pestivirus, induced the loss of IRF3 by inhibiting the transcription of IRF3 mRNA. In the present study, we show that endogenous IRF3 and IRF3 expressed from a cytomegalovirus (CMV) promoter are depleted in the presence of CSFV by means of N(pro), while CSFV does not inhibit CMV promoter-driven protein expression. We also demonstrate that CSFV does not reduce the transcriptional activity of the IRF3 promoter and does not affect the stability of IRF3 mRNA. In fact, CSFV N(pro) induces proteasomal degradation of IRF3, as demonstrated by proteasome inhibition studies. Furthermore, N(pro) coprecipitates with IRF3, suggesting that the proteasomal degradation of IRF3 is induced by a direct or indirect interaction with N(pro). Finally, we show that N(pro) does not downregulate IRF7 expression.

  • Classical Swine Fever Virus Npro Interacts with Interferon Regulatory Factor 3 and Induces Its Proteasomal Degradation
    Journal of Virology, 2007
    Co-Authors: Oliver Bauhofer, Jon Duri Tratschin, Artur Summerfield, Martin A. Hofmann, Yoshihiro Sakoda, Nicolas Ruggli
    Abstract:

    Viruses have evolved a multitude of strategies to subvert the innate immune system by interfering with components of the alpha/beta interferon (IFN-α/β) induction and signaling pathway. It is well established that the pestiviruses prevent IFN-α/β induction in their primary target cells, such as epitheloidal and endothelial cells, macrophages, and conventional dendritic cells, a phenotype mediated by the viral protein Npro. Central players in the IFN-α/β induction cascade are interferon regulatory factor 3 (IRF3) and IRF7. Recently, it was proposed that classical swine fever virus (CSFV), the porcine pestivirus, induced the loss of IRF3 by inhibiting the transcription of IRF3 mRNA. In the present study, we show that endogenous IRF3 and IRF3 expressed from a cytomegalovirus (CMV) promoter are depleted in the presence of CSFV by means of Npro, while CSFV does not inhibit CMV promoter-driven protein expression. We also demonstrate that CSFV does not reduce the transcriptional activity of the IRF3 promoter and does not affect the stability of IRF3 mRNA. In fact, CSFV Npro induces proteasomal degradation of IRF3, as demonstrated by proteasome inhibition studies. Furthermore, Npro coprecipitates with IRF3, suggesting that the proteasomal degradation of IRF3 is induced by a direct or indirect interaction with Npro. Finally, we show that Npro does not downregulate IRF7 expression.

John T. Patton - One of the best experts on this subject based on the ideXlab platform.

  • rotavirus nsp1 mediates degradation of interferon regulatory factors through targeting of the dimerization domain
    Journal of Virology, 2013
    Co-Authors: Michelle M Arnold, Mario Barro, John T. Patton
    Abstract:

    Rotavirus nonstructural protein NSP1 can inhibit expression of interferon (IFN) and IFN-stimulated gene products by inducing proteasome-mediated degradation of IFN-regulatory factors (IRFs), including IRF3, IRF5, and IRF7. All IRF proteins share an N-terminal DNA-binding domain (DBD), and IRF3, IRF5, and IRF7 contain a similar C-proximal IRF association domain (IAD) that mediates IRF dimerization. An autoinhibitory domain (ID) at the extreme C terminus interacts with the IAD, burying residues necessary for IRF dimerization. Phosphorylation of serine/threonine residues in the ID induces charge repulsions that unmask the IAD, enabling IRF dimerization and subsequent nuclear translocation. To define the region of IRF proteins targeted for degradation by NSP1, we generated IRF3 and IRF7 truncation mutants and transiently expressed each with simian SA11-4F NSP1. These assays indicated that the IAD represented a necessary and sufficient target for degradation. Because NSP1 did not mediate degradation of truncated forms of the IAD, NSP1 likely requires a structurally intact IAD for recognition and targeting of IRF proteins. IRF9, which contains an IAD-like region that directs interactions with signal inducer and activator of transcription (STAT) proteins, was also targeted for degradation by NSP1, while IRF1, which lacks an IAD, was not. Analysis of mutant forms of IRF3 unable to undergo dimerization or that were constitutively dimeric showed that both were targeted for degradation by NSP1. These results indicate that SA11-4F NSP1 can induce degradation of inactive and activated forms of IAD-containing IRF proteins (IRF3 to IRF9), allowing a multipronged attack on IFN-based pathways that promote antiviral innate and adaptive immune responses.

  • Rotavirus NSP1 Inhibits Expression of Type I Interferon by Antagonizing the Function of Interferon Regulatory Factors IRF3, IRF5, and IRF7
    Journal of Virology, 2007
    Co-Authors: Mario Barro, John T. Patton
    Abstract:

    Secretion of interferon (IFN) by virus-infected cells is essential for activating autocrine and paracrine pathways that promote cellular transition to an antiviral state. In most mammalian cells, IFN production is initiated by the activation of constitutively expressed IFN regulatory factor 3, IRF3, which in turn leads to the induction of IRF7, the “master regulator” of IFN type I synthesis (alpha/beta IFN). Previous studies established that rotavirus NSP1 antagonizes IFN signaling by inducing IRF3 degradation. In the present study, we have determined that, in comparison to wild-type rotaviruses, rotaviruses encoding defective NSP1 grow to lower titers in some cell lines and that this poor growth phenotype is due to their failure to suppress IFN expression. Furthermore, we provide evidence that rotaviruses encoding wild-type NSP1 subvert IFN signaling by inducing the degradation of not only IRF3, but also IRF7, with both events occurring through proteasome-dependent processes that proceed with similar efficiencies. The capacity of NSP1 to induce IRF7 degradation may allow rotavirus to move across the gut barrier by enabling the virus to replicate in specialized trafficking cells (dendritic cells and macrophages) that constitutively express IRF7. Along with IRF3 and IRF7, NSP1 was found to induce the degradation of IRF5, a factor that upregulates IFN expression and that is involved in triggering apoptosis during viral infection. Our analysis suggests that NSP1 mediates the degradation of IRF3, IRF5, and IRF7 by recognizing a common element of IRF proteins, thereby allowing NSP1 to act as a broad-spectrum antagonist of IRF function.

Oliver Bauhofer - One of the best experts on this subject based on the ideXlab platform.

  • classical swine fever virus npro interacts with interferon regulatory factor 3 and induces its proteasomal degradation
    Journal of Virology, 2007
    Co-Authors: Oliver Bauhofer, Jon Duri Tratschin, Artur Summerfield, Martin A. Hofmann, Yoshihiro Sakoda, Nicolas Ruggli
    Abstract:

    Viruses have evolved a multitude of strategies to subvert the innate immune system by interfering with components of the alpha/beta interferon (IFN-alpha/beta) induction and signaling pathway. It is well established that the pestiviruses prevent IFN-alpha/beta induction in their primary target cells, such as epitheloidal and endothelial cells, macrophages, and conventional dendritic cells, a phenotype mediated by the viral protein N(pro). Central players in the IFN-alpha/beta induction cascade are interferon regulatory factor 3 (IRF3) and IRF7. Recently, it was proposed that classical swine fever virus (CSFV), the porcine pestivirus, induced the loss of IRF3 by inhibiting the transcription of IRF3 mRNA. In the present study, we show that endogenous IRF3 and IRF3 expressed from a cytomegalovirus (CMV) promoter are depleted in the presence of CSFV by means of N(pro), while CSFV does not inhibit CMV promoter-driven protein expression. We also demonstrate that CSFV does not reduce the transcriptional activity of the IRF3 promoter and does not affect the stability of IRF3 mRNA. In fact, CSFV N(pro) induces proteasomal degradation of IRF3, as demonstrated by proteasome inhibition studies. Furthermore, N(pro) coprecipitates with IRF3, suggesting that the proteasomal degradation of IRF3 is induced by a direct or indirect interaction with N(pro). Finally, we show that N(pro) does not downregulate IRF7 expression.

  • Classical Swine Fever Virus Npro Interacts with Interferon Regulatory Factor 3 and Induces Its Proteasomal Degradation
    Journal of Virology, 2007
    Co-Authors: Oliver Bauhofer, Jon Duri Tratschin, Artur Summerfield, Martin A. Hofmann, Yoshihiro Sakoda, Nicolas Ruggli
    Abstract:

    Viruses have evolved a multitude of strategies to subvert the innate immune system by interfering with components of the alpha/beta interferon (IFN-α/β) induction and signaling pathway. It is well established that the pestiviruses prevent IFN-α/β induction in their primary target cells, such as epitheloidal and endothelial cells, macrophages, and conventional dendritic cells, a phenotype mediated by the viral protein Npro. Central players in the IFN-α/β induction cascade are interferon regulatory factor 3 (IRF3) and IRF7. Recently, it was proposed that classical swine fever virus (CSFV), the porcine pestivirus, induced the loss of IRF3 by inhibiting the transcription of IRF3 mRNA. In the present study, we show that endogenous IRF3 and IRF3 expressed from a cytomegalovirus (CMV) promoter are depleted in the presence of CSFV by means of Npro, while CSFV does not inhibit CMV promoter-driven protein expression. We also demonstrate that CSFV does not reduce the transcriptional activity of the IRF3 promoter and does not affect the stability of IRF3 mRNA. In fact, CSFV Npro induces proteasomal degradation of IRF3, as demonstrated by proteasome inhibition studies. Furthermore, Npro coprecipitates with IRF3, suggesting that the proteasomal degradation of IRF3 is induced by a direct or indirect interaction with Npro. Finally, we show that Npro does not downregulate IRF7 expression.

Paul H.a. Quax - One of the best experts on this subject based on the ideXlab platform.

  • IRF3 and IRF7 mediate neovascularization via inflammatory cytokines.
    Journal of Cellular and Molecular Medicine, 2019
    Co-Authors: Karin H. Simons, H.a.b. Peters, J.w. Jukema, Margreet R. De Vries, Rob C.m. De Jong, Paul H.a. Quax
    Abstract:

    Objective To elucidate the role of interferon regulatory factor (IRF)3 and IRF7 in neovascularization. Methods Unilateral hind limb ischaemia was induced in IRF3-/- , Irf7-/- and C57BL/6 mice by ligation of the left common femoral artery. Post-ischaemic blood flow recovery in the paw was measured with laser Doppler perfusion imaging. Soleus, adductor and gastrocnemius muscles were harvested to investigate angiogenesis and arteriogenesis and inflammation. Results Post-ischaemic blood flow recovery was decreased in IRF3-/- and Irf7-/- mice compared to C57BL/6 mice at all time points up to and including sacrifice, 28 days after surgery (t28). This was supported by a decrease in angiogenesis and arteriogenesis in soleus and adductor muscles of IRF3-/- and Irf7-/- mice at t28. Furthermore, the number of macrophages around arterioles in adductor muscles was decreased in IRF3-/- and Irf7-/- mice at t28. In addition, mRNA expression levels of pro-inflammatory cytokines (tnfα, il6, ccl2) and growth factor receptor (vegfr2), were decreased in gastrocnemius muscles of IRF3-/- and Irf7-/- mice compared to C57BL/6 mice. Conclusion Deficiency of IRF3 and IRF7 results in impaired post-ischaemic blood flow recovery caused by attenuated angiogenesis and arteriogenesis linked to a lack of inflammatory components in ischaemic tissue. Therefore, IRF3 and IRF7 are essential regulators of neovascularization.

  • A protective role of IRF3 and IRF7 signalling downstream TLRs in the development of vein graft disease via type I interferons
    Journal of Internal Medicine, 2017
    Co-Authors: Karin H. Simons, H.a.b. Peters, J.w. Jukema, M.r. De Vries, Paul H.a. Quax
    Abstract:

    Background Toll like receptors (TLR) play an important role in vein graft disease (VGD). Interferon regulatory factors (IRF) 3 and 7 are the transcriptional regulators of type I interferons (IFN) and type I IFN responsive genes and are downstream factors of TLRs. Relatively little is known with regard to the interplay of IRFs and TLRs in VGD development. The aim of this study was to investigate the role of IRF3 and IRF7 signaling downstream TLRs and the effect of IRF3 and IRF7 in VGD. Methods and Results In vitro activation of TLR3 induced IRF3 and IRF7 dependent IFNβ expression in bone marrow macrophages and vascular smooth muscle cells. Activation of TLR4 showed to regulate pro-inflammatory cytokines via IRF3. Vein graft surgery was performed in IRF3−/−, Irf7−/− and control mice. After 14 days IRF3−/− vein grafts had an increased vessel wall thickness compared to both control (P = 0.01) and Irf7−/− (P = 0.02) vein grafts. After 28 days, vessel wall thickness increased in IRF3−/− (P = 0.0003) and Irf7−/− (P = 0.04) compared to control vein grafts and also increased in Irf7−/− compared to IRF3−/− vein grafts (P = 0.02). Immunohistochemical analysis showed a significant higher influx of macrophages after 14 days in IRF3−/− vein grafts and after 28 days in Irf7−/− vein grafts compared to control vein grafts. Conclusions The present study is the first to describe a protective role of both IRF3 and IRF7 in VGD. IRFs regulate VGD downstream TLRs since IRF3−/− and Irf7−/− vein grafts show increased vessel wall thickening after respectively 14 and 28 days after surgery.

  • abstract 370 interferon regulatory factors 3 and 7 regulate vein graft remodeling and vascular inflammation
    Arteriosclerosis Thrombosis and Vascular Biology, 2014
    Co-Authors: Margreet R. De Vries, Paul H.a. Quax, Jacco C Karper, Erna Peters, Tineke C Van Der Pouw Kraan, Rob C De Jong, Jaap F Hamming, A J G Horrevoets
    Abstract:

    Introduction: Type I interferons (IFN) are implicated in the development of vascular proliferative diseases. Pathway analysis by gene set enrichment analysis of hypercholesterolemic ApoE3*Leiden murine vein grafts revealed that the type I IFN pathway belonged to the top 15 of significant regulated pathways. The transcriptional regulators of type I IFN and type I IFN responsive genes are the interferon regulatory factors (IRF). Activation of TLR3 results in activation of type I IFN in a IRF3 and IRF7 dependent manner. TLR3 has been shown to be protective in vascular remodeling. The aim of this study was to investigate the role of IRF3 and IRF7 on vein graft remodeling. Methods and Results: The importance of IRFs in vein graft remodeling is illustrated by the increase in vein graft thickening in IRF3-/- and Irf7-/- mice in comparison to control mice (n=9/group, IRF3-/- ; 39%, p=0.185, Irf7-/- ; 68% p=0.003). Also an increase in outward remodeling ( IRF3-/- ; 26%, p=0.081, Irf7-/- ; 42%, p=0.049) was observed comparable to that of Tlr3-/- (n=8, 52%, p<0.001) Immunohistochemical analysis revealed that both IRF3-/- and Irf7-/- mice showed a significant higher influx of macrophages in the vessel wall than the control mice whereas the Irf7-/- mice also showed a significant decrease in collagen content. RNA levels of typical type I IFN responsive genes such as Mx1, Ifit1-3 and Oas2 were down regulated in the knockout vein grafts in comparison to control vein grafts. Activation of both IRF3-/- and Irf7-/- bone marrow derived macrophages with LPS and poly:(IC) resulted in a significant increase in TNFα production. Conclusions: IRFs regulates vein graft remodeling since IRF3-/- and especially Irf7-/- vein grafts show increased vessel wall thickening and outward remodeling. This increased remodeling is the result of a pro-inflammatory response as reflected by the increase in macrophages in the vein graft wall.

Jon Duri Tratschin - One of the best experts on this subject based on the ideXlab platform.

  • classical swine fever virus npro interacts with interferon regulatory factor 3 and induces its proteasomal degradation
    Journal of Virology, 2007
    Co-Authors: Oliver Bauhofer, Jon Duri Tratschin, Artur Summerfield, Martin A. Hofmann, Yoshihiro Sakoda, Nicolas Ruggli
    Abstract:

    Viruses have evolved a multitude of strategies to subvert the innate immune system by interfering with components of the alpha/beta interferon (IFN-alpha/beta) induction and signaling pathway. It is well established that the pestiviruses prevent IFN-alpha/beta induction in their primary target cells, such as epitheloidal and endothelial cells, macrophages, and conventional dendritic cells, a phenotype mediated by the viral protein N(pro). Central players in the IFN-alpha/beta induction cascade are interferon regulatory factor 3 (IRF3) and IRF7. Recently, it was proposed that classical swine fever virus (CSFV), the porcine pestivirus, induced the loss of IRF3 by inhibiting the transcription of IRF3 mRNA. In the present study, we show that endogenous IRF3 and IRF3 expressed from a cytomegalovirus (CMV) promoter are depleted in the presence of CSFV by means of N(pro), while CSFV does not inhibit CMV promoter-driven protein expression. We also demonstrate that CSFV does not reduce the transcriptional activity of the IRF3 promoter and does not affect the stability of IRF3 mRNA. In fact, CSFV N(pro) induces proteasomal degradation of IRF3, as demonstrated by proteasome inhibition studies. Furthermore, N(pro) coprecipitates with IRF3, suggesting that the proteasomal degradation of IRF3 is induced by a direct or indirect interaction with N(pro). Finally, we show that N(pro) does not downregulate IRF7 expression.

  • Classical Swine Fever Virus Npro Interacts with Interferon Regulatory Factor 3 and Induces Its Proteasomal Degradation
    Journal of Virology, 2007
    Co-Authors: Oliver Bauhofer, Jon Duri Tratschin, Artur Summerfield, Martin A. Hofmann, Yoshihiro Sakoda, Nicolas Ruggli
    Abstract:

    Viruses have evolved a multitude of strategies to subvert the innate immune system by interfering with components of the alpha/beta interferon (IFN-α/β) induction and signaling pathway. It is well established that the pestiviruses prevent IFN-α/β induction in their primary target cells, such as epitheloidal and endothelial cells, macrophages, and conventional dendritic cells, a phenotype mediated by the viral protein Npro. Central players in the IFN-α/β induction cascade are interferon regulatory factor 3 (IRF3) and IRF7. Recently, it was proposed that classical swine fever virus (CSFV), the porcine pestivirus, induced the loss of IRF3 by inhibiting the transcription of IRF3 mRNA. In the present study, we show that endogenous IRF3 and IRF3 expressed from a cytomegalovirus (CMV) promoter are depleted in the presence of CSFV by means of Npro, while CSFV does not inhibit CMV promoter-driven protein expression. We also demonstrate that CSFV does not reduce the transcriptional activity of the IRF3 promoter and does not affect the stability of IRF3 mRNA. In fact, CSFV Npro induces proteasomal degradation of IRF3, as demonstrated by proteasome inhibition studies. Furthermore, Npro coprecipitates with IRF3, suggesting that the proteasomal degradation of IRF3 is induced by a direct or indirect interaction with Npro. Finally, we show that Npro does not downregulate IRF7 expression.