Poxvirus Protein N1L Targets the I-κB Kinase Complex, Inhibits Signaling to NF-κB by the Tumor Necrosis Factor Superfamily of Receptors, and Inhibits NF-κB and IRF3 Signaling by Toll-like Receptors

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dc.contributor.authorDiPerna, Gary
dc.contributor.authorStack, Julianne
dc.contributor.authorBowie, Andrew G
dc.contributor.authorBoyd, Annemarie
dc.contributor.authorKotwal, Girish
dc.contributor.authorZhang, Zhouning
dc.contributor.authorArvikar, Sheila
dc.contributor.authorLatz, Eicke
dc.contributor.authorFitzgerald, Katherine A
dc.contributor.authorMarshall, William L
dc.date.accessioned2021-10-08T07:20:48Z
dc.date.available2021-10-08T07:20:48Z
dc.date.issued2004
dc.description.abstractPoxviruses encode proteins that suppress host immune responses, including secreted decoy receptors for pro-inflammatory cytokines such as interleukin-1 (IL-1) and the vaccinia virus proteins A46R and A52R that inhibit intracellular signaling by members of the IL-1 receptor (IL-1R) and Toll-like receptor (TLR) family. In vivo, the TLRs mediate the innate immune response by serving as pathogen recognition receptors, whose oligomerized intracellular Toll/IL-1 receptor (TIR) domains can initiate innate immune signaling. A family of TIR domain-containing adapter molecules transduces signals from engaged receptors that ultimately activate NF-kappaB and/or interferon regulatory factor 3 (IRF3) to induce pro-inflammatory cytokines. Data base searches detected a significant similarity between the N1L protein of vaccinia virus and A52R, a poxvirus inhibitor of TIR signaling. Compared with other poxvirus virulence factors, the poxvirus N1L protein strongly affects virulence in vivo; however, the precise target of N1L was previously unknown. Here we show that N1L suppresses NF-kappaB activation following engagement of Toll/IL-1 receptors, tumor necrosis factor receptors, and lymphotoxin receptors. N1L inhibited receptor-, adapter-, TRAF-, and IKK-alpha and IKK-beta-dependent signaling to NF-kappaB. N1L associated with several components of the multisubunit I-kappaB kinase complex, most strongly associating with the kinase, TANK-binding kinase 1 (TBK1). Together these findings are consistent with the hypothesis that N1L disrupts signaling to NF-kappaB by Toll/IL-1Rs and TNF superfamily receptors by targeting the IKK complex for inhibition. Furthermore, N1L inhibited IRF3 signaling, which is also regulated by TBK1. These studies define a role for N1L as an immunomodulator of innate immunity by targeting components of NF-kappaB and IRF3 signaling pathways.
dc.identifier.apacitationDiPerna, G., Stack, J., Bowie, A. G., Boyd, A., Kotwal, G., Zhang, Z., ... Marshall, W. L. (2004). Poxvirus Protein N1L Targets the I-κB Kinase Complex, Inhibits Signaling to NF-κB by the Tumor Necrosis Factor Superfamily of Receptors, and Inhibits NF-κB and IRF3 Signaling by Toll-like Receptors. <i>The Journal of Biological Chemistry</i>, 279(35), 36570 - 36578. http://hdl.handle.net/11427/35008en_ZA
dc.identifier.chicagocitationDiPerna, Gary, Julianne Stack, Andrew G Bowie, Annemarie Boyd, Girish Kotwal, Zhouning Zhang, Sheila Arvikar, Eicke Latz, Katherine A Fitzgerald, and William L Marshall "Poxvirus Protein N1L Targets the I-κB Kinase Complex, Inhibits Signaling to NF-κB by the Tumor Necrosis Factor Superfamily of Receptors, and Inhibits NF-κB and IRF3 Signaling by Toll-like Receptors." <i>The Journal of Biological Chemistry</i> 279, 35. (2004): 36570 - 36578. http://hdl.handle.net/11427/35008en_ZA
dc.identifier.citationDiPerna, G., Stack, J., Bowie, A.G., Boyd, A., Kotwal, G., Zhang, Z., Arvikar, S. & Latz, E. et al. 2004. Poxvirus Protein N1L Targets the I-κB Kinase Complex, Inhibits Signaling to NF-κB by the Tumor Necrosis Factor Superfamily of Receptors, and Inhibits NF-κB and IRF3 Signaling by Toll-like Receptors. <i>The Journal of Biological Chemistry.</i> 279(35):36570 - 36578. http://hdl.handle.net/11427/35008en_ZA
dc.identifier.issn0021-9258
dc.identifier.issn1083-351X
dc.identifier.ris TY - Journal Article AU - DiPerna, Gary AU - Stack, Julianne AU - Bowie, Andrew G AU - Boyd, Annemarie AU - Kotwal, Girish AU - Zhang, Zhouning AU - Arvikar, Sheila AU - Latz, Eicke AU - Fitzgerald, Katherine A AU - Marshall, William L AB - Poxviruses encode proteins that suppress host immune responses, including secreted decoy receptors for pro-inflammatory cytokines such as interleukin-1 (IL-1) and the vaccinia virus proteins A46R and A52R that inhibit intracellular signaling by members of the IL-1 receptor (IL-1R) and Toll-like receptor (TLR) family. In vivo, the TLRs mediate the innate immune response by serving as pathogen recognition receptors, whose oligomerized intracellular Toll/IL-1 receptor (TIR) domains can initiate innate immune signaling. A family of TIR domain-containing adapter molecules transduces signals from engaged receptors that ultimately activate NF-kappaB and/or interferon regulatory factor 3 (IRF3) to induce pro-inflammatory cytokines. Data base searches detected a significant similarity between the N1L protein of vaccinia virus and A52R, a poxvirus inhibitor of TIR signaling. Compared with other poxvirus virulence factors, the poxvirus N1L protein strongly affects virulence in vivo; however, the precise target of N1L was previously unknown. Here we show that N1L suppresses NF-kappaB activation following engagement of Toll/IL-1 receptors, tumor necrosis factor receptors, and lymphotoxin receptors. N1L inhibited receptor-, adapter-, TRAF-, and IKK-alpha and IKK-beta-dependent signaling to NF-kappaB. N1L associated with several components of the multisubunit I-kappaB kinase complex, most strongly associating with the kinase, TANK-binding kinase 1 (TBK1). Together these findings are consistent with the hypothesis that N1L disrupts signaling to NF-kappaB by Toll/IL-1Rs and TNF superfamily receptors by targeting the IKK complex for inhibition. Furthermore, N1L inhibited IRF3 signaling, which is also regulated by TBK1. These studies define a role for N1L as an immunomodulator of innate immunity by targeting components of NF-kappaB and IRF3 signaling pathways. DA - 2004 DB - OpenUCT DP - University of Cape Town IS - 35 J1 - The Journal of Biological Chemistry LK - https://open.uct.ac.za PY - 2004 SM - 0021-9258 SM - 1083-351X T1 - Poxvirus Protein N1L Targets the I-κB Kinase Complex, Inhibits Signaling to NF-κB by the Tumor Necrosis Factor Superfamily of Receptors, and Inhibits NF-κB and IRF3 Signaling by Toll-like Receptors TI - Poxvirus Protein N1L Targets the I-κB Kinase Complex, Inhibits Signaling to NF-κB by the Tumor Necrosis Factor Superfamily of Receptors, and Inhibits NF-κB and IRF3 Signaling by Toll-like Receptors UR - http://hdl.handle.net/11427/35008 ER - en_ZA
dc.identifier.urihttp://hdl.handle.net/11427/35008
dc.identifier.vancouvercitationDiPerna G, Stack J, Bowie AG, Boyd A, Kotwal G, Zhang Z, et al. Poxvirus Protein N1L Targets the I-κB Kinase Complex, Inhibits Signaling to NF-κB by the Tumor Necrosis Factor Superfamily of Receptors, and Inhibits NF-κB and IRF3 Signaling by Toll-like Receptors. The Journal of Biological Chemistry. 2004;279(35):36570 - 36578. http://hdl.handle.net/11427/35008.en_ZA
dc.language.isoeng
dc.publisher.departmentDivision of Medical Virology
dc.publisher.facultyFaculty of Health Sciences
dc.sourceThe Journal of Biological Chemistry
dc.source.journalissue35
dc.source.journalvolume279
dc.source.pagination36570 - 36578
dc.source.urihttps://dx.doi.org/10.1074/jbc.M400567200
dc.subject.otherCell Line
dc.subject.otherCytokines
dc.subject.otherDNA-Binding Proteins
dc.subject.otherDose-Response Relationship, Drug
dc.subject.otherGenes, Reporter
dc.subject.otherGenetic Vectors
dc.subject.otherHumans
dc.subject.otherI-kappa B Kinase
dc.subject.otherInterferon Regulatory Factor-3
dc.subject.otherInterleukin-1
dc.subject.otherMembrane Glycoproteins
dc.subject.otherNF-kappa B
dc.subject.otherPlasmids
dc.subject.otherPoxviridae
dc.subject.otherPrecipitin Tests
dc.subject.otherProtein Binding
dc.titlePoxvirus Protein N1L Targets the I-κB Kinase Complex, Inhibits Signaling to NF-κB by the Tumor Necrosis Factor Superfamily of Receptors, and Inhibits NF-κB and IRF3 Signaling by Toll-like Receptors
dc.typeJournal Article
uct.type.publicationResearch
uct.type.resourceJournal Article
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