Genomes and Genes
interferon regulatory factor 3
Summary: An interferon regulatory factor that is expressed constitutively and undergoes POST-TRANSLATIONAL MODIFICATION following viral infection. PHOSPHORYLATION of IRF-3 causes the protein to be translocated from the CYTOPLASM to CELL NUCLEUS where it binds DNA, and activates transcription.
- Szymanski M, Fiebach A, Tratschin J, Gut M, Ramanujam V, Gottipati K, et al. Zinc binding in pestivirus N(pro) is required for interferon regulatory factor 3 interaction and degradation. J Mol Biol. 2009;391:438-49 pubmed publisher..N(pro) also targets interferon regulatory factor 3 (IRF3), a transcription factor for alpha/beta interferon genes, and promotes its proteasomal ..
- Zeng W, Xu M, Liu S, Sun L, Chen Z. Key role of Ubc5 and lysine-63 polyubiquitination in viral activation of IRF3. Mol Cell. 2009;36:315-25 pubmed publisher..Furthermore, we show that replacement of endogenous ubiquitin with its K63R mutant abolishes viral activation of IRF3, demonstrating that K63 polyubiquitination plays a key role in IRF3 activation. ..
- tenOever B, Sharma S, Zou W, Sun Q, Grandvaux N, Julkunen I, et al. Activation of TBK1 and IKKvarepsilon kinases by vesicular stomatitis virus infection and the role of viral ribonucleoprotein in the development of interferon antiviral immunity. J Virol. 2004;78:10636-49 pubmed..the noncanonical IKK-related kinases TBK1 and IKKepsilon have been shown to phosphorylate and activate interferon regulatory factor 3 (IRF-3) and IRF-7, leading to the production of alpha/beta interferons and the development of a ..
- Yu S, Chen J, Wu M, Chen H, Kato N, Yuan Z. Hepatitis B virus polymerase inhibits RIG-I- and Toll-like receptor 3-mediated beta interferon induction in human hepatocytes through interference with interferon regulatory factor 3 activation and dampening of the interaction between TBK1/IKKepsilon. J Gen Virol. 2010;91:2080-90 pubmed publisher..Taken together, these findings reveal a novel role of HBV polymerase in HBV counteraction of IFN-beta production in human hepatocytes. ..
- Holm G, Pruijssers A, Li L, Danthi P, Sherry B, Dermody T. Interferon regulatory factor 3 attenuates reovirus myocarditis and contributes to viral clearance. J Virol. 2010;84:6900-8 pubmed publisher..In cell culture models, the antiviral transcription factor interferon regulatory factor 3 (IRF-3) enhances reovirus-induced apoptosis following activation via retinoic acid inducible gene I ..
- Lei X, Liu X, Ma Y, Sun Z, Yang Y, Jin Q, et al. The 3C protein of enterovirus 71 inhibits retinoid acid-inducible gene I-mediated interferon regulatory factor 3 activation and type I interferon responses. J Virol. 2010;84:8051-61 pubmed publisher..This precludes the recruitment of an adaptor IPS-1 by RIG-I and subsequent nuclear translocation of interferon regulatory factor 3. An R84Q or V154S substitution in the RNA binding motifs has no effect...
- Sen N, Sommer M, Che X, White K, Ruyechan W, Arvin A. Varicella-zoster virus immediate-early protein 62 blocks interferon regulatory factor 3 (IRF3) phosphorylation at key serine residues: a novel mechanism of IRF3 inhibition among herpesviruses. J Virol. 2010;84:9240-53 pubmed publisher..Thus, IE62 has two critical but discrete roles following VZV entry: to induce expression of VZV genes and to disarm the IFN-dependent antiviral defense through a novel mechanism that prevents IRF3 phosphorylation. ..
- Li H, Zheng Z, Zhou P, Zhang B, Shi Z, Hu Q, et al. The cysteine protease domain of porcine reproductive and respiratory syndrome virus non-structural protein 2 antagonizes interferon regulatory factor 3 activation. J Gen Virol. 2010;91:2947-58 pubmed publisher..These findings suggest that Nsp2 is likely to play an important role in subversion of IRF-3-dependent innate antiviral defences, providing a basis for elucidating the mechanisms underlying PRRSV pathogenesis...
- Panne D, Maniatis T, Harrison S. An atomic model of the interferon-beta enhanceosome. Cell. 2007;129:1111-23 pubmed..Contacts with virtually every nucleotide pair account for the evolutionary invariance of the enhancer sequence. ..
- Liu X, Wei B, Shi H, Shan Y, Wang C. Tom70 mediates activation of interferon regulatory factor 3 on mitochondria. Cell Res. 2010;20:994-1011 pubmed publisher..Consequently, this leads to the activation of TANK-binding kinase 1 (TBK1) and phosphorylation of interferon regulatory factor 3 (IRF3), both of which constitutively associate with cytosolic chaperone Hsp90...
- Lin L, Noyce R, Pham T, Wilson J, Sisson G, Michalak T, et al. Replication of subgenomic hepatitis C virus replicons in mouse fibroblasts is facilitated by deletion of interferon regulatory factor 3 and expression of liver-specific microRNA 122. J Virol. 2010;84:9170-80 pubmed publisher..miR-122 and IRF-3 are independent host factors that are capable of influencing HCV replication, and our findings could help to establish mouse models and other cell systems that support HCV growth and particle formation. ..
- Menachery V, Pasieka T, Leib D. Interferon regulatory factor 3-dependent pathways are critical for control of herpes simplex virus type 1 central nervous system infection. J Virol. 2010;84:9685-94 pubmed publisher..Furthermore, this work underscores the necessity to evaluate multiple routes of infection and animal models in order to fully determine the role of host resistance factors in pathogenesis. ..
- Menachery V, Leib D. Control of herpes simplex virus replication is mediated through an interferon regulatory factor 3-dependent pathway. J Virol. 2009;83:12399-406 pubmed publisher..Together, these results demonstrate a critical role for IRF-3-mediated pathways in controlling HSV-1 replication in cells of the murine immune system. ..
- Siu K, Kok K, Ng M, Poon V, Yuen K, Zheng B, et al. Severe acute respiratory syndrome coronavirus M protein inhibits type I interferon production by impeding the formation of TRAF3.TANK.TBK1/IKKepsilon complex. J Biol Chem. 2009;284:16202-9 pubmed publisher..Taken together, our findings reveal a new mechanism by which SARS coronavirus circumvents the production of type I interferons. ..
- Thomas B, Lindsay M, Dagher H, Freezer N, Li D, Ghildyal R, et al. Transforming growth factor-beta enhances rhinovirus infection by diminishing early innate responses. Am J Respir Cell Mol Biol. 2009;41:339-47 pubmed publisher..TGF-beta may act as an endogenous immunosuppressant promoting virus replication and inflammation during the evolution of acute severe asthma associated with rhinovirus infection. ..
- Clark K, Plater L, Peggie M, Cohen P. Use of the pharmacological inhibitor BX795 to study the regulation and physiological roles of TBK1 and IkappaB kinase epsilon: a distinct upstream kinase mediates Ser-172 phosphorylation and activation. J Biol Chem. 2009;284:14136-46 pubmed publisher..and IKKepsilon, blocked the phosphorylation, nuclear translocation, and transcriptional activity of interferon regulatory factor 3 and, hence, the production of interferon-beta in macrophages stimulated with poly(I:C) or ..
- Myskiw C, Arsenio J, van Bruggen R, Deschambault Y, Cao J. Vaccinia virus E3 suppresses expression of diverse cytokines through inhibition of the PKR, NF-kappaB, and IRF3 pathways. J Virol. 2009;83:6757-68 pubmed publisher..Collectively, these results indicate that E3 suppresses distinct but interlinked host signaling pathways to inhibit the expression of a diverse array of cytokines. ..
- Oshansky C, Krunkosky T, Barber J, Jones L, Tripp R. Respiratory syncytial virus proteins modulate suppressors of cytokine signaling 1 and 3 and the type I interferon response to infection by a toll-like receptor pathway. Viral Immunol. 2009;22:147-61 pubmed publisher..These findings indicate that RSV surface proteins signal through the TLR pathway, suggesting that this may be an important mechanism to reduce type I IFN expression to aid virus replication. ..
- Fleetwood A, Dinh H, Cook A, Hertzog P, Hamilton J. GM-CSF- and M-CSF-dependent macrophage phenotypes display differential dependence on type I interferon signaling. J Leukoc Biol. 2009;86:411-21 pubmed publisher..Collectively, these findings demonstrate that constitutive and LPS-induced type I IFN play significant roles in regulating the differences in phenotype and function between BMM and GM-BMM. ..
- Cloutier N, Flamand L. Kaposi sarcoma-associated herpesvirus latency-associated nuclear antigen inhibits interferon (IFN) beta expression by competing with IFN regulatory factor-3 for binding to IFNB promoter. J Biol Chem. 2010;285:7208-21 pubmed publisher..The ability of LANA-1 to inhibit IFNB gene expression highlights a new role for this protein in cellular gene modulation and immune evasion strategies...
- Shirota H, Petrenko L, Hattori T, Klinman D. Contribution of IRF-3 mediated IFNbeta production to DNA vaccine dependent cellular immune responses. Vaccine. 2009;27:2144-9 pubmed publisher..This defect was remedied by the co-delivery of an IFNbeta encoding plasmid. These findings suggest that the IRF-3/IFNbeta pathways are key to the induction of cellular immunity following DNA vaccination. ..
- Konno H, Yamamoto T, Yamazaki K, Gohda J, Akiyama T, Semba K, et al. TRAF6 establishes innate immune responses by activating NF-kappaB and IRF7 upon sensing cytosolic viral RNA and DNA. PLoS ONE. 2009;4:e5674 pubmed publisher..Given its essential role in signaling by various receptors involved in the acquired immune system, TRAF6 represents a key molecule in innate and antigen-specific immune responses against viral infection. ..
- Park S, Song H, Youn H. Suppression of the TRIF-dependent signaling pathway of toll-like receptors by isoliquiritigenin in RAW264.7 macrophages. Mol Cells. 2009;28:365-8 pubmed publisher..ILG inhibited nuclear factor-kappaB and interferon regulatory factor 3 activation induced by lipopolysaccharide or polyinosinic-polycytidylic acid...
- Shi X, Wang L, Zhi Y, Xing G, Zhao D, Deng R, et al. Porcine reproductive and respiratory syndrome virus (PRRSV) could be sensed by professional beta interferon-producing system and had mechanisms to inhibit this action in MARC-145 cells. Virus Res. 2010;153:151-6 pubmed publisher..In conclusion, our results suggested that PRRSV could be sensed by professional IFN-beta-producing system and had mechanisms to inhibit this action in MARC-145 cells...
- Carrigan S, Junkins R, Yang Y, MacNeil A, Richardson C, Johnston B, et al. IFN regulatory factor 3 contributes to the host response during Pseudomonas aeruginosa lung infection in mice. J Immunol. 2010;185:3602-9 pubmed publisher..aeruginosa infection. Thus, IRF3 is an integral component in the host defense against P. aeruginosa lung infection. ..
- Haye K, Burmakina S, Moran T, Garcia Sastre A, Fernandez Sesma A. The NS1 protein of a human influenza virus inhibits type I interferon production and the induction of antiviral responses in primary human dendritic and respiratory epithelial cells. J Virol. 2009;83:6849-62 pubmed publisher..Lastly, C-terminal truncations in the NS1 protein of human influenza virus are sufficient to make the virus attenuated and more immunogenic, supporting its use as a live attenuated influenza vaccine in humans. ..
- DeFilippis V, Alvarado D, Sali T, Rothenburg S, Fruh K. Human cytomegalovirus induces the interferon response via the DNA sensor ZBP1. J Virol. 2010;84:585-98 pubmed publisher..response in infected cells that includes transcription of the beta interferon gene via activation of interferon regulatory factor 3 (IRF3)...
- Lecat A, Piette J, Legrand Poels S. The protein Nod2: an innate receptor more complex than previously assumed. Biochem Pharmacol. 2010;80:2021-31 pubmed publisher..Recently, Nod2 has been also shown to be exquisitely tuned to detect mycobacterial infections and mount a protective immunity against these pathogens. ..
- Yang P, An H, Liu X, Wen M, Zheng Y, Rui Y, et al. The cytosolic nucleic acid sensor LRRFIP1 mediates the production of type I interferon via a beta-catenin-dependent pathway. Nat Immunol. 2010;11:487-94 pubmed publisher..Therefore, LRRFIP1 and its downstream partner beta-catenin constitute another coactivator pathway for IRF3-mediated production of type I interferon. ..
- Verstrepen L, Verhelst K, Van Loo G, Carpentier I, Ley S, Beyaert R. Expression, biological activities and mechanisms of action of A20 (TNFAIP3). Biochem Pharmacol. 2010;80:2009-20 pubmed publisher..Here we review the expression and biological activities of A20, as well as the underlying molecular mechanisms. ..
- Zeng W, Sun L, Jiang X, Chen X, Hou F, Adhikari A, et al. Reconstitution of the RIG-I pathway reveals a signaling role of unanchored polyubiquitin chains in innate immunity. Cell. 2010;141:315-30 pubmed publisher..Our results delineate the mechanism of RIG-I activation, identify CARD domains as a ubiquitin sensor, and demonstrate that unanchored K63-polyubiquitin chains are signaling molecules in antiviral innate immunity...
- Sen A, Feng N, Ettayebi K, Hardy M, Greenberg H. IRF3 inhibition by rotavirus NSP1 is host cell and virus strain dependent but independent of NSP1 proteasomal degradation. J Virol. 2009;83:10322-35 pubmed publisher..Thus, NSP1's ability to degrade IRF3 is host cell dependent and is independent of NSP1 proteasomal degradation. ..
- Tanaka H, Yoshida M, Nishiumi S, Ohnishi N, Kobayashi K, Yamamoto K, et al. The CagA protein of Helicobacter pylori suppresses the functions of dendritic cell in mice. Arch Biochem Biophys. 2010;498:35-42 pubmed publisher..These data suggest that CagA protein negatively regulates the functions of DC via CagA phosphorylation and that cagA-positive H. pylori strains suppress host immune responses resulting in their chronic colonization of the stomach. ..
- Zheng L, Yu C, Zhang Z, Yang C, Cai X. Expression of interferon regulatory factor 1, 3, and 7 in primary Sjögren syndrome. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2009;107:661-8 pubmed publisher..Also, IRF1-positive cells exist in the epithelial islands, lymphocytes, and ductal epithelial cells of the parotid glands of individuals affected by pSS, but are limited to the ductal epithelial cells of healthy control subjects. ..
- Kim H, Seed B. The transcription factor MafB antagonizes antiviral responses by blocking recruitment of coactivators to the transcription factor IRF3. Nat Immunol. 2010;11:743-50 pubmed publisher..Higher expression of MafB in human pancreatic islet beta cells might increase cellular vulnerability to viral infections associated with the etiology of type 1 diabetes. ..
- Yanai H, Ban T, Wang Z, Choi M, Kawamura T, Negishi H, et al. HMGB proteins function as universal sentinels for nucleic-acid-mediated innate immune responses. Nature. 2009;462:99-103 pubmed publisher..show a more profound defect, accompanied by impaired activation of the transcription factors interferon regulatory factor 3 (IRF3) and nuclear factor (NF)-kappaB...
- Li Y, Li C, Xue P, Zhong B, Mao A, Ran Y, et al. ISG56 is a negative-feedback regulator of virus-triggered signaling and cellular antiviral response. Proc Natl Acad Sci U S A. 2009;106:7945-50 pubmed publisher..These results suggest that ISG56 is a mediator of negative-feedback regulation of virus-triggered induction of type I IFNs and cellular antiviral responses...
- Soucy Faulkner A, Mukawera E, Fink K, Martel A, Jouan L, Nzengue Y, et al. Requirement of NOX2 and reactive oxygen species for efficient RIG-I-mediated antiviral response through regulation of MAVS expression. PLoS Pathog. 2010;6:e1000930 pubmed publisher..Taken together these data reveal a new facet to the regulation of the innate host defense against viruses through the identification of an unrecognized role of NOX2 and ROS. ..
- Saira K, Zhou Y, Jones C. The infected cell protein 0 encoded by bovine herpesvirus 1 (bICP0) associates with interferon regulatory factor 7 and consequently inhibits beta interferon promoter activity. J Virol. 2009;83:3977-81 pubmed publisher..Furthermore, bICP0 inhibits the ability of IRF7 to trans-activate the IFN-beta promoter in the absence of IRF3 expression. The interaction between bICP0 and IRF7 correlates with reduced trans-activation of the IFN-beta promoter by IRF7...
- Tatematsu M, Ishii A, Oshiumi H, Horiuchi M, Inagaki F, Seya T, et al. A molecular mechanism for Toll-IL-1 receptor domain-containing adaptor molecule-1-mediated IRF-3 activation. J Biol Chem. 2010;285:20128-36 pubmed publisher..Upon stimulation of TLR3/4, TICAM-1 oligomerizes through the TIR domain and the C-terminal region, which may break the intramolecular association and induce a conformational change that allows TBK1 access to TICAM-1. ..
- Park S, Youn H. Suppression of homodimerization of toll-like receptor 4 by isoliquiritigenin. Phytochemistry. 2010;71:1736-40 pubmed publisher..and, subsequently, activation of downstream signaling pathways including nuclear factor-kappa B and interferon regulatory factor 3. TLR4 dimerization may be an early regulatory event in activating signaling pathways induced by LPS...
- Suzuki S, Zhou Y, Refaat A, Takasaki I, Koizumi K, Yamaoka S, et al. Human T cell lymphotropic virus 1 manipulates interferon regulatory signals by controlling the TAK1-IRF3 and IRF4 pathways. J Biol Chem. 2010;285:4441-6 pubmed publisher..Together, HTLV-1 manipulates IFN signaling by regulating both positive and negative IRFs. ..
- Melroe G, Silva L, Schaffer P, Knipe D. Recruitment of activated IRF-3 and CBP/p300 to herpes simplex virus ICP0 nuclear foci: Potential role in blocking IFN-beta induction. Virology. 2007;360:305-21 pubmed..Therefore, ICP0 provides an example of how viruses can block IFN-beta induction by sequestration of important transcription factors essential for the host response. ..
- Zhao Y, Rivieccio M, Lutz S, Scemes E, Brosnan C. The TLR3 ligand polyI: C downregulates connexin 43 expression and function in astrocytes by a mechanism involving the NF-kappaB and PI3 kinase pathways. Glia. 2006;54:775-85 pubmed..vectors containing a super-repressor of NF-kappaB (NF-kappaB SR) construct or a dominant negative interferon regulatory factor 3 (dnIRF3) construct showed that inhibition of both transcription factors also blocked the effects of pI:..
- Sweeney S, Kimbler T, Firestein G. Synoviocyte innate immune responses: II. Pivotal role of IFN regulatory factor 3. J Immunol. 2010;184:7162-8 pubmed publisher..Targeting synoviocyte IRF3 represents a potential approach to suppress diverse mediators while limiting suppression of IRF7-mediated immune responses. ..
- Borysiewicz E, Fil D, Dlaboga D, O Donnell J, Konat G. Phosphodiesterase 4B2 gene is an effector of Toll-like receptor signaling in astrocytes. Metab Brain Dis. 2009;24:481-91 pubmed publisher..These results demonstrate that the phosphodiesterase 4B2 gene is an effector of Toll-like receptor signaling in astrocytes, and that its up-regulation at the protein level is controlled by complex mechanisms...
- Koarai A, Sugiura H, Yanagisawa S, Ichikawa T, Minakata Y, Matsunaga K, et al. Oxidative stress enhances toll-like receptor 3 response to double-stranded RNA in airway epithelial cells. Am J Respir Cell Mol Biol. 2010;42:651-60 pubmed publisher..Modulation of this pathway may be a therapeutic target for viral-induced exacerbations of COPD. ..
- Hara Y, Shiraishi A, Kobayashi T, Kadota Y, Shirakata Y, Hashimoto K, et al. Alteration of TLR3 pathways by glucocorticoids may be responsible for immunosusceptibility of human corneal epithelial cells to viral infections. Mol Vis. 2009;15:937-48 pubmed..In addition, we determined the effects of immunosuppressive drugs on the innate responses...
- Johnsen I, Nguyen T, Bergstroem B, Fitzgerald K, Anthonsen M. The tyrosine kinase c-Src enhances RIG-I (retinoic acid-inducible gene I)-elicited antiviral signaling. J Biol Chem. 2009;284:19122-31 pubmed publisher..The interaction between c-Src and TRAF3 was found to occur within the RING domain of TRAF3. Taken together, our results suggest that c-Src enhances RIG-I-mediated signaling, acting at the level of TRAF3. ..
- Le V, Trilling M, Zimmermann A, Hengel H. Mouse cytomegalovirus inhibits beta interferon (IFN-beta) gene expression and controls activation pathways of the IFN-beta enhanceosome. J Gen Virol. 2008;89:1131-41 pubmed publisher..Our findings indicate that the MCMV-mediated downregulation of IFN transcription in fibroblasts relies on a large arsenal of inhibitory mechanisms targeting each pathway that contributes to the multiprotein enhanceosome complex. ..
- Rose K, Elliott R, Martinez Sobrido L, Garcia Sastre A, Weiss S. Murine coronavirus delays expression of a subset of interferon-stimulated genes. J Virol. 2010;84:5656-69 pubmed publisher..Transcription from an IRF-3-responsive promoter was partially inhibited by MHV; however, IRF-3 was transported to the nucleus and bound DNA in MHV-infected cells superinfected with SeV. ..