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PMID: 17568778 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

SINTBAD, a novel component of innate antiviral immunity, shares a TBK1-binding domain with NAP1 and TANK.

The EMBO journal ·Vol. 26 ·No. 13 ·2007-07-11 ·Pages 3180-90

Ryzhakov G, Randow F

Abstract

The expression of antiviral genes during infection is controlled by inducible transcription factors such as IRF3 (interferon regulatory factor). Activation of IRF3 requires its phosphorylation by TBK1 (TANK-binding kinase) or IKKi (inhibitor of nuclear factor kappaB kinase, inducible). We have identified a new and essential component of this pathway, the adaptor protein SINTBAD (similar to NAP1 TBK1 adaptor). SINTBAD constitutively binds TBK1 and IKKi but not related kinases. Upon infection with Sendai virus, SINTBAD is essential for the efficient induction of IRF-dependent transcription, as are two further TBK1 adaptors, TANK and NAP1. We identified a conserved TBK1/IKKi-binding domain (TBD) in the three adaptors, predicted to form an alpha-helix with residues essential for kinase binding clustering on one side. Isolated TBDs compete with adaptor binding to TBK1 and prevent poly(I:C)-induced IRF-dependent transcription. Our results suggest that efficient signal transduction upon viral infection requires SINTBAD, TANK and NAP1 because they link TBK1 and IKKi to virus-activated signalling cascades.

MeSH Terms
Adaptor Proteins, Signal Transducing/chemistry,genetics,metabolism Amino Acid Sequence Animals Binding Sites Cell Line Conserved Sequence Enzyme Activation Humans I-kappa B Kinase/metabolism Immunity, Innate/drug effects,immunology Interferon Regulatory Factors/metabolism Membrane Proteins/chemistry,metabolism Mice Molecular Sequence Data Poly I-C/pharmacology Protein Binding Protein Serine-Threonine Kinases/metabolism Proteins/chemistry,metabolism RNA Interference Sendai virus/immunology Sequence Alignment tRNA Methyltransferases
Chemicals
Adaptor Proteins, Signal Transducing Interferon Regulatory Factors Membrane Proteins Nckap1 protein, mouse Proteins SINTBAD protein, mouse TANK protein, human TBKBP1 protein, human TRMO protein, human tRNA Methyltransferases Protein Serine-Threonine Kinases TBK1 protein, human I-kappa B Kinase Poly I-C
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Ryzhakov Grigory
Medical Research Council Laboratory of Molecular Biology, Cambridge, UK.
Randow Felix
References (58)
58 references, click to expand
  1. A cytokine-responsive IkappaB kinase that activates the transcription factor NF-kappaB.
    Nature. 1997 Aug 7;388(6642):548-54 PMID: 9252186
  2. Modulation of the interferon antiviral response by the TBK1/IKKi adaptor protein TANK.
    J Biol Chem. 2007 Apr 20;282(16):11817-26 PMID: 17327220
  3. IKK-1 and IKK-2: cytokine-activated IkappaB kinases essential for NF-kappaB activation.
    Science. 1997 Oct 31;278(5339):860-6 PMID: 9346484
  4. IkappaB kinase-beta: NF-kappaB activation and complex formation with IkappaB kinase-alpha and NIK.
    Science. 1997 Oct 31;278(5339):866-9 PMID: 9346485
  5. Complementation cloning of NEMO, a component of the IkappaB kinase complex essential for NF-kappaB activation.
    Cell. 1998 Jun 26;93(7):1231-40 PMID: 9657155
  6. IKK-gamma is an essential regulatory subunit of the IkappaB kinase complex.
    Nature. 1998 Sep 17;395(6699):297-300 PMID: 9751060
  7. IkappaB kinase (IKK)-associated protein 1, a common component of the heterogeneous IKK complex.
    Mol Cell Biol. 1999 Feb;19(2):1526-38 PMID: 9891086
  8. Identification of a cell protein (FIP-3) as a modulator of NF-kappaB activity and as a target of an adenovirus inhibitor of tumor necrosis factor alpha-induced apoptosis.
    Proc Natl Acad Sci U S A. 1999 Feb 2;96(3):1042-7 PMID: 9927690
  9. Limb and skin abnormalities in mice lacking IKKalpha.
    Science. 1999 Apr 9;284(5412):313-6 PMID: 10195895
  10. Abnormal morphogenesis but intact IKK activation in mice lacking the IKKalpha subunit of IkappaB kinase.
    Science. 1999 Apr 9;284(5412):316-20 PMID: 10195896
  11. Severe liver degeneration in mice lacking the IkappaB kinase 2 gene.
    Science. 1999 Apr 9;284(5412):321-5 PMID: 10195897
  12. Embryonic lethality, liver degeneration, and impaired NF-kappa B activation in IKK-beta-deficient mice.
    Immunity. 1999 Apr;10(4):421-9 PMID: 10229185
  13. IKK1-deficient mice exhibit abnormal development of skin and skeleton.
    Genes Dev. 1999 May 15;13(10):1322-8 PMID: 10346820
  14. NF-kappaB activation by a signaling complex containing TRAF2, TANK and TBK1, a novel IKK-related kinase.
    EMBO J. 1999 Dec 1;18(23):6694-704 PMID: 10581243
  15. Severe liver degeneration and lack of NF-kappaB activation in NEMO/IKKgamma-deficient mice.
    Genes Dev. 2000 Apr 1;14(7):854-62 PMID: 10766741
  16. NAK is an IkappaB kinase-activating kinase.
    Nature. 2000 Apr 13;404(6779):778-82 PMID: 10783893
  17. Genomic rearrangement in NEMO impairs NF-kappaB activation and is a cause of incontinentia pigmenti. The International Incontinentia Pigmenti (IP) Consortium.
    Nature. 2000 May 25;405(6785):466-72 PMID: 10839543
  18. IKKepsilon is part of a novel PMA-inducible IkappaB kinase complex.
    Mol Cell. 2000 Mar;5(3):513-22 PMID: 10882136
  19. Female mice heterozygous for IKK gamma/NEMO deficiencies develop a dermatopathy similar to the human X-linked disorder incontinentia pigmenti.
    Mol Cell. 2000 Jun;5(6):969-79 PMID: 10911991
  20. NEMO/IKK gamma-deficient mice model incontinentia pigmenti.
    Mol Cell. 2000 Jun;5(6):981-92 PMID: 10911992
  21. Selective inhibition of NF-kappaB activation by a peptide that blocks the interaction of NEMO with the IkappaB kinase complex.
    Science. 2000 Sep 1;289(5484):1550-4 PMID: 10968790
  22. Deficiency of T2K leads to apoptotic liver degeneration and impaired NF-kappaB-dependent gene transcription.
    EMBO J. 2000 Sep 15;19(18):4976-85 PMID: 10990461
  23. A novel X-linked disorder of immune deficiency and hypohidrotic ectodermal dysplasia is allelic to incontinentia pigmenti and due to mutations in IKK-gamma (NEMO).
    Am J Hum Genet. 2000 Dec;67(6):1555-62 PMID: 11047757
  24. X-linked anhidrotic ectodermal dysplasia with immunodeficiency is caused by impaired NF-kappaB signaling.
    Nat Genet. 2001 Mar;27(3):277-85 PMID: 11242109
  25. Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3.
    Nature. 2001 Oct 18;413(6857):732-8 PMID: 11607032
  26. Cutting edge: a novel Toll/IL-1 receptor domain-containing adapter that preferentially activates the IFN-beta promoter in the Toll-like receptor signaling.
    J Immunol. 2002 Dec 15;169(12):6668-72 PMID: 12471095
  27. TICAM-1, an adaptor molecule that participates in Toll-like receptor 3-mediated interferon-beta induction.
    Nat Immunol. 2003 Feb;4(2):161-7 PMID: 12539043
  28. IKKepsilon and TBK1 are essential components of the IRF3 signaling pathway.
    Nat Immunol. 2003 May;4(5):491-6 PMID: 12692549
  29. Triggering the interferon antiviral response through an IKK-related pathway.
    Science. 2003 May 16;300(5622):1148-51 PMID: 12702806
  30. Role of adaptor TRIF in the MyD88-independent toll-like receptor signaling pathway.
    Science. 2003 Aug 1;301(5633):640-3 PMID: 12855817
  31. Identification of Lps2 as a key transducer of MyD88-independent TIR signalling.
    Nature. 2003 Aug 14;424(6950):743-8 PMID: 12872135
  32. Selective contribution of IFN-alpha/beta signaling to the maturation of dendritic cells induced by double-stranded RNA or viral infection.
    Proc Natl Acad Sci U S A. 2003 Sep 16;100(19):10872-7 PMID: 12960379
  33. Identification of NAP1, a regulatory subunit of IkappaB kinase-related kinases that potentiates NF-kappaB signaling.
    Mol Cell Biol. 2003 Nov;23(21):7780-93 PMID: 14560022
  34. IFN-regulatory factor 3-dependent gene expression is defective in Tbk1-deficient mouse embryonic fibroblasts.
    Proc Natl Acad Sci U S A. 2004 Jan 6;101(1):233-8 PMID: 14679297
  35. A physical and functional map of the human TNF-alpha/NF-kappa B signal transduction pathway.
    Nat Cell Biol. 2004 Feb;6(2):97-105 PMID: 14743216
  36. The roles of two IkappaB kinase-related kinases in lipopolysaccharide and double stranded RNA signaling and viral infection.
    J Exp Med. 2004 Jun 21;199(12):1641-50 PMID: 15210742
  37. Differential requirement for TANK-binding kinase-1 in type I interferon responses to toll-like receptor activation and viral infection.
    J Exp Med. 2004 Jun 21;199(12):1651-8 PMID: 15210743
  38. The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responses.
    Nat Immunol. 2004 Jul;5(7):730-7 PMID: 15208624
  39. Signaling to NF-kappaB.
    Genes Dev. 2004 Sep 15;18(18):2195-224 PMID: 15371334
  40. CHUK, a new member of the helix-loop-helix and leucine zipper families of interacting proteins, contains a serine-threonine kinase catalytic domain.
    Cell Mol Biol Res. 1995;41(6):537-49 PMID: 8777433
  41. Identification and characterization of an IkappaB kinase.
    Cell. 1997 Jul 25;90(2):373-83 PMID: 9244310
  42. The IKKbeta subunit of IkappaB kinase (IKK) is essential for nuclear factor kappaB activation and prevention of apoptosis.
    J Exp Med. 1999 Jun 7;189(11):1839-45 PMID: 10359587
  43. IKK-i, a novel lipopolysaccharide-inducible kinase that is related to IkappaB kinases.
    Int Immunol. 1999 Aug;11(8):1357-62 PMID: 10421793
  44. Cutting Edge: NF-kappaB-activating kinase-associated protein 1 participates in TLR3/Toll-IL-1 homology domain-containing adapter molecule-1-mediated IFN regulatory factor 3 activation.
    J Immunol. 2005 Jan 1;174(1):27-30 PMID: 15611223
  45. High-throughput mapping of a dynamic signaling network in mammalian cells.
    Science. 2005 Mar 11;307(5715):1621-5 PMID: 15761153
  46. Cell type-specific involvement of RIG-I in antiviral response.
    Immunity. 2005 Jul;23(1):19-28 PMID: 16039576
  47. Identification and characterization of MAVS, a mitochondrial antiviral signaling protein that activates NF-kappaB and IRF 3.
    Cell. 2005 Sep 9;122(5):669-82 PMID: 16125763
  48. VISA is an adapter protein required for virus-triggered IFN-beta signaling.
    Mol Cell. 2005 Sep 16;19(6):727-40 PMID: 16153868
  49. IPS-1, an adaptor triggering RIG-I- and Mda5-mediated type I interferon induction.
    Nat Immunol. 2005 Oct;6(10):981-8 PMID: 16127453
  50. Cardif is an adaptor protein in the RIG-I antiviral pathway and is targeted by hepatitis C virus.
    Nature. 2005 Oct 20;437(7062):1167-72 PMID: 16177806
  51. Essential role of mda-5 in type I IFN responses to polyriboinosinic:polyribocytidylic acid and encephalomyocarditis picornavirus.
    Proc Natl Acad Sci U S A. 2006 May 30;103(22):8459-64 PMID: 16714379
  52. Key function for the Ubc13 E2 ubiquitin-conjugating enzyme in immune receptor signaling.
    Nat Immunol. 2006 Sep;7(9):962-70 PMID: 16862162
  53. IRFs: master regulators of signalling by Toll-like receptors and cytosolic pattern-recognition receptors.
    Nat Rev Immunol. 2006 Sep;6(9):644-58 PMID: 16932750
  54. Regulation and function of IKK and IKK-related kinases.
    Sci STKE. 2006 Oct 17;2006(357):re13 PMID: 17047224
  55. Cutting edge: Role of TANK-binding kinase 1 and inducible IkappaB kinase in IFN responses against viruses in innate immune cells.
    J Immunol. 2006 Nov 1;177(9):5785-9 PMID: 17056502
  56. NAK-associated protein 1 participates in both the TLR3 and the cytoplasmic pathways in type I IFN induction.
    J Immunol. 2006 Dec 15;177(12):8676-83 PMID: 17142768
  57. Local treatment with the selective IkappaB kinase beta inhibitor NEMO-binding domain peptide ameliorates synovial inflammation.
    Arthritis Res Ther. 2006;8(4):R86 PMID: 16684367
  58. The IkappaB kinase complex (IKK) contains two kinase subunits, IKKalpha and IKKbeta, necessary for IkappaB phosphorylation and NF-kappaB activation.
    Cell. 1997 Oct 17;91(2):243-52 PMID: 9346241
Article Info
Journal
The EMBO journal
Abbr.
EMBO J
ISSN
0261-4189
DOI
10.1038/sj.emboj.7601743
Published
2007-07-11
Epub
2007-00-14
Pages
3180-90
Language
English
Region
England
NLM ID
8208664
PMCID
PMC1914091
Subset
IM
Grants
Medical Research Council · MC_U105170648 · United Kingdom
External Links
PubMed source DOI: 10.1038/sj.emboj.7601743 PMC Full Text View journal details
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