Poxvirus protein N1L targets the I-kappaB kinase complex, inhibits signaling to NF-kappaB by the tumor necrosis factor superfamily of receptors, and inhibits NF-kappaB and IRF3 signaling by toll-like receptors
Authors
DiPerna, GaryStack, Julianne
Bowie, Andrew G.
Boyd, Annemarie
Kotwal, Girish J.
Zhang, Zhouning
Arvikar, Sheila
Latz, Eicke
Fitzgerald, Katherine A.
Marshall, William L.
UMass Chan Affiliations
Department of Medicine, Division of Infectious Diseases and ImmunologyDocument Type
Journal ArticlePublication Date
2004-06-25Keywords
Cell LineCytokines
DNA-Binding Proteins
Dose-Response Relationship, Drug
Genes, Reporter
Genetic Vectors
Humans
I-kappa B Kinase
Interferon Regulatory Factor-3
Interleukin-1
Membrane Glycoproteins
NF-kappa B
Plasmids
Poxviridae
Precipitin Tests
Protein Binding
Protein Biosynthesis
Protein Structure, Tertiary
Protein-Serine-Threonine Kinases
Receptors, Cell Surface
Signal Transduction
Toll-Like Receptors
Transcription Factors
Transcription, Genetic
Transfection
Tumor Necrosis Factor-alpha
Viral Proteins
Immunology and Infectious Disease
Metadata
Show full item recordAbstract
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.Source
J Biol Chem. 2004 Aug 27;279(35):36570-8. Epub 2004 Jun 23. Link to article on publisher's siteDOI
10.1074/jbc.M400567200Permanent Link to this Item
http://hdl.handle.net/20.500.14038/35261PubMed ID
15215253Related Resources
Link to Article in PubMedae974a485f413a2113503eed53cd6c53
10.1074/jbc.M400567200
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