Functional Dissection of the TBK1 Molecular Network

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2011 Sep 21

PMID 21931631

Citations 72

Authors

Adriana Goncalves

Tilmann Burckstummer

Evelyn Dixit

Ruth Scheicher

Maria W Gorna

Evren Karayel

Cristina Sugar

Alexey Stukalov

Tiina Berg

Robert Kralovics

Melanie Planyavsky

Keiryn L Bennett

Jacques Colinge

Giulio Superti-Furga

Affiliations

Soon will be listed here.

Abstract

TANK-binding kinase 1 (TBK1) and inducible IκB-kinase (IKK-i) are central regulators of type-I interferon induction. They are associated with three adaptor proteins called TANK, Sintbad (or TBKBP1) and NAP1 (or TBKBP2, AZI2) whose functional relationship to TBK1 and IKK-i is poorly understood. We performed a systematic affinity purification-mass spectrometry approach to derive a comprehensive TBK1/IKK-i molecular network. The most salient feature of the network is the mutual exclusive interaction of the adaptors with the kinases, suggesting distinct alternative complexes. Immunofluorescence data indicated that the individual adaptors reside in different subcellular locations. TANK, Sintbad and NAP1 competed for binding of TBK1. The binding site for all three adaptors was mapped to the C-terminal coiled-coil 2 region of TBK1. Point mutants that affect binding of individual adaptors were used to reconstitute TBK1/IKK-i-deficient cells and dissect the functional relevance of the individual kinase-adaptor edges within the network. Using a microarray-derived gene expression signature of TBK1 in response virus infection or poly(I∶C) stimulation, we found that TBK1 activation was strictly dependent on the integrity of the TBK1/TANK interaction.

Citing Articles

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References

Mao A, Li S, Zhong B, Li Y, Yan J, Li Q . Virus-triggered ubiquitination of TRAF3/6 by cIAP1/2 is essential for induction of interferon-beta (IFN-beta) and cellular antiviral response. J Biol Chem. 2010; 285(13):9470-9476. PMC: 2843197. DOI: 10.1074/jbc.M109.071043. View

Soulat D, Burckstummer T, Westermayer S, Goncalves A, Bauch A, Stefanovic A . The DEAD-box helicase DDX3X is a critical component of the TANK-binding kinase 1-dependent innate immune response. EMBO J. 2008; 27(15):2135-46. PMC: 2453059. DOI: 10.1038/emboj.2008.126. View

Pomerantz J, Baltimore D . NF-kappaB activation by a signaling complex containing TRAF2, TANK and TBK1, a novel IKK-related kinase. EMBO J. 1999; 18(23):6694-704. PMC: 1171732. DOI: 10.1093/emboj/18.23.6694. View

Unterholzner L, Keating S, Baran M, Horan K, Jensen S, Sharma S . IFI16 is an innate immune sensor for intracellular DNA. Nat Immunol. 2010; 11(11):997-1004. PMC: 3142795. DOI: 10.1038/ni.1932. View

Fernandes-Alnemri T, Yu J, Datta P, Wu J, Alnemri E . AIM2 activates the inflammasome and cell death in response to cytoplasmic DNA. Nature. 2009; 458(7237):509-13. PMC: 2862225. DOI: 10.1038/nature07710. View

Bouwmeester T, Bauch A, Ruffner H, Angrand P, Bergamini G, Croughton K . A physical and functional map of the human TNF-alpha/NF-kappa B signal transduction pathway. Nat Cell Biol. 2004; 6(2):97-105. DOI: 10.1038/ncb1086. View

Schroder M, Baran M, Bowie A . Viral targeting of DEAD box protein 3 reveals its role in TBK1/IKKepsilon-mediated IRF activation. EMBO J. 2008; 27(15):2147-57. PMC: 2516890. DOI: 10.1038/emboj.2008.143. View

Panne D, Maniatis T, Harrison S . An atomic model of the interferon-beta enhanceosome. Cell. 2007; 129(6):1111-23. PMC: 2020837. DOI: 10.1016/j.cell.2007.05.019. View

Perry A, Chow E, Goodnough J, Yeh W, Cheng G . Differential requirement for TANK-binding kinase-1 in type I interferon responses to toll-like receptor activation and viral infection. J Exp Med. 2004; 199(12):1651-8. PMC: 2212814. DOI: 10.1084/jem.20040528. View

10.

Hacker H, Redecke V, Blagoev B, Kratchmarova I, Hsu L, Wang G . Specificity in Toll-like receptor signalling through distinct effector functions of TRAF3 and TRAF6. Nature. 2005; 439(7073):204-7. DOI: 10.1038/nature04369. View

11.

Cheng G, Baltimore D . TANK, a co-inducer with TRAF2 of TNF- and CD 40L-mediated NF-kappaB activation. Genes Dev. 1996; 10(8):963-73. DOI: 10.1101/gad.10.8.963. View

12.

Sharma S, tenOever B, Grandvaux N, Zhou G, Lin R, Hiscott J . Triggering the interferon antiviral response through an IKK-related pathway. Science. 2003; 300(5622):1148-51. DOI: 10.1126/science.1081315. View

13.

Pichlmair A, Reis e Sousa C . Innate recognition of viruses. Immunity. 2007; 27(3):370-83. DOI: 10.1016/j.immuni.2007.08.012. View

14.

Thurston T, Ryzhakov G, Bloor S, von Muhlinen N, Randow F . The TBK1 adaptor and autophagy receptor NDP52 restricts the proliferation of ubiquitin-coated bacteria. Nat Immunol. 2009; 10(11):1215-21. DOI: 10.1038/ni.1800. View

15.

Hacker H, Karin M . Regulation and function of IKK and IKK-related kinases. Sci STKE. 2006; 2006(357):re13. DOI: 10.1126/stke.3572006re13. View

16.

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(21):14136-46. PMC: 2682862. DOI: 10.1074/jbc.M109.000414. View

17.

Ryzhakov G, Randow F . SINTBAD, a novel component of innate antiviral immunity, shares a TBK1-binding domain with NAP1 and TANK. EMBO J. 2007; 26(13):3180-90. PMC: 1914091. DOI: 10.1038/sj.emboj.7601743. View

18.

Haura E, Muller A, Breitwieser F, Li J, Grebien F, Colinge J . Using iTRAQ combined with tandem affinity purification to enhance low-abundance proteins associated with somatically mutated EGFR core complexes in lung cancer. J Proteome Res. 2010; 10(1):182-90. PMC: 3017669. DOI: 10.1021/pr100863f. View

19.

Sasai M, Shingai M, Funami K, Yoneyama M, Fujita T, Matsumoto M . NAK-associated protein 1 participates in both the TLR3 and the cytoplasmic pathways in type I IFN induction. J Immunol. 2006; 177(12):8676-83. DOI: 10.4049/jimmunol.177.12.8676. View

20.

Burckstummer T, Bennett K, Preradovic A, Schutze G, Hantschel O, Superti-Furga G . An efficient tandem affinity purification procedure for interaction proteomics in mammalian cells. Nat Methods. 2006; 3(12):1013-9. DOI: 10.1038/nmeth968. View