Involvement of the ubiquitin-like domain of TBK1/IKK-i kinases in regulation of IFN-inducible genes

Ikeda, Fumiyo; Hecker, Christina; Rozenknop, Alexis; Nordmeier, Rolf Dietrich; Rogov, Vladimir V.; Hofmann, Kay; Akira, Shizuo; Dötsch, Volker; Đikić, Ivan

doi:10.1038/sj.emboj.7601773

Cited by 108 publications

(103 citation statements)

References 45 publications

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“…Whether this modification of TANK is essential for LPS-mediated IRF3 activation remains unclear [21]. TBK1 and IKK-e also harbor a ubiquitin-like domain (ULD), adjacent to their N-terminal kinase domain and located upstream of their C-terminal coil-coil domains [82]. The ULD does not seem to bind to known ubiquitin-binding domains but is nevertheless crucial for TBK1 and IKK-e substrate recognition and kinase activity [82].…”

Section: Reviewmentioning

confidence: 99%

“…TBK1 and IKK-e also harbor a ubiquitin-like domain (ULD), adjacent to their N-terminal kinase domain and located upstream of their C-terminal coil-coil domains [82]. The ULD does not seem to bind to known ubiquitin-binding domains but is nevertheless crucial for TBK1 and IKK-e substrate recognition and kinase activity [82]. Therefore, these recent studies strongly indicate that optimal TBK1-and IKK-emediated phosphorylation requires distinct functional domains and highlight the importance of TANK nondegradative polyubiquitination for subsequent IFN gene induction.…”

Section: Reviewmentioning

confidence: 99%

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Are the IKKs and IKK-related kinases TBK1 and IKK-ɛ similarly activated?

Chau

Gioia

Gatot

et al. 2008

Trends in Biochemical Sciences

208

171

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The IkB kinases (IKKs) IKK-a and IKK-b, and the IKK-related kinases TBK1 and IKK-e, have essential roles in innate immunity through signal-induced activation of NF-kB, IRF3 and IRF7, respectively. Although the signaling events within these pathways have been extensively studied, the mechanisms of IKK and IKK-related complex assembly and activation remain poorly defined. Recent data provide insight into the requirement for scaffold proteins in complex assembly; NF-kB essential modulator coordinates some IKK complexes, whereas TANK, NF-kB-activating kinase-associated protein 1 (NAP1) or similar to NAP1 TBK1 adaptor (SINTBAD) assemble TBK1 and IKK-e complexes. The different scaffold proteins undergo similar post-translational modifications, including phosphorylation and non-degradative polyubiquitylation. Moreover, increasing evidence indicates that distinct scaffold proteins assemble IKK, and potentially TBK1 and IKK-e subcomplexes, in a stimulus-specific manner, which might be a mechanism to achieve specificity. Review GlossaryCaspase-recruitment domain (CARD): the CARD is found in some initiator caspases, but also in some adaptor proteins, and mediates protein-protein interactions. Classical and alternative NF-kB-activating pathways: the classical pathway is triggered by various stimuli, including proinflammatory cytokines and TLR ligands, and leads to the activation of the IKK complex that includes IKK-a and IKK-b and also the scaffold protein NEMO. This complex targets the inhibitory IkBa protein for phosphorylation, which is followed by its degradation through the proteasome pathway. NF-kB heterodimers (typically composed of p50 and p65) subsequently move into the nucleus to drive the expression of proinflammatory molecules and chemokines. The alternative pathway is triggered by stimuli such as lymphotoxin-b and requires the kinase NIK in addition to an IKK-a homodimer. NEMO is dispensable for this pathway to be activated. The targeted inhibitory molecule is p100 instead of IkBa, and the NFkB heterodimers are typically composed of p52 and RelB. The target genes of this pathway are required for adaptive immunity. Conventional myeloid and plasmacytoid dendritic cells: dendritic cells (DCs) take up antigens, are activated and migrate to lymphoid tissues in order to present the antigenic peptides on the MHC molecules. They can be broadly divided into plasmacytoid DCs (pDCs) and conventional myeloid DCs, based on the expression of a variety of cell surface markers and their responses to pathogen molecules. pDCs are defined as a subset of cells, the appearance under the microscope of which is similar to that of plasmablasts. These cells are the main producers of type I IFNs in response to viral infections. CpG DNAs: CpG DNAs are DNA oligodeoxynucleotide sequences that include a cytosine-guanosine sequence and some flanking nucleotides. The CpG DNAs induce innate immunity through binding to the TLR9 receptor. Cytosolic NF-kB and IRF activating pathways: these pathways include the RIG-I family (comprising MDA5 and RI...

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Section: Reviewmentioning

confidence: 99%

Section: Reviewmentioning

confidence: 99%

Are the IKKs and IKK-related kinases TBK1 and IKK-ɛ similarly activated?

Chau

Gioia

Gatot

et al. 2008

Trends in Biochemical Sciences

208

171

View full text Add to dashboard Cite

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“…Deletion or mutation of the ULD in TBK1 or IKKε severely impairs kinase activation and substrate phosphorylation in cells (22,23). Furthermore, the integrity of the ULD in IKKβ is not only required for kinase activity (24) but was shown also to confer substrate specificity in conjunction with the adjacent SDD (25).…”

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confidence: 99%

“…TBK1 contains a predicted ubiquitin-like domain (ULD) (22) that is located between the N-terminal kinase domain (KD) and the C-terminal scaffolding/dimerization domain (SDD), a domain arrangement that appears to be shared among the IKK family of kinases (3). Deletion or mutation of the ULD in TBK1 or IKKε severely impairs kinase activation and substrate phosphorylation in cells (22,23).…”

mentioning

confidence: 99%

Molecular basis of Tank-binding kinase 1 activation by transautophosphorylation

Ma¹,

Helgason

Phung³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

183

227

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Tank-binding kinase (TBK)1 plays a central role in innate immunity: it serves as an integrator of multiple signals induced by receptormediated pathogen detection and as a modulator of IFN levels. Efforts to better understand the biology of this key immunological factor have intensified recently as growing evidence implicates aberrant TBK1 activity in a variety of autoimmune diseases and cancers. Nevertheless, key molecular details of TBK1 regulation and substrate selection remain unanswered. Here, structures of phosphorylated and unphosphorylated human TBK1 kinase and ubiquitin-like domains, combined with biochemical studies, indicate a molecular mechanism of activation via transautophosphorylation. These TBK1 structures are consistent with the tripartite architecture observed recently for the related kinase IKKβ, but domain contributions toward target recognition appear to differ for the two enzymes. In particular, both TBK1 autoactivation and substrate specificity are likely driven by signal-dependent colocalization events. Phosphorylation promotes the dimerization and nuclear translocation of these transcription factors that stimulate production of type I interferons (IFNs) (1,3,5). Recent studies have identified an additional role for TBK1 in the xenophagic elimination of bacteria (6-9) and better-defined how cross-talk within the IKK family regulates innate immune response (10).Under pathological conditions, IKK-mediated pathways can also be activated inappropriately by endogenous signals, contributing to inflammatory disorders and oncogenesis (11,12). Whereas canonical IKKs have long been recognized as bridges between chronic inflammation and cancer, IKK-related kinases more recently have also been implicated in cell transformation and tumor progression (13). TBK1 has been of particular interest, given its identification both as an activator of the oncogenic AKT kinase (14-18) and as an essential factor in KRAS-driven cancers (19).TBK1 activity is regulated by phosphorylation on S172 within the classical kinase activation loop. Serine-to-alanine substitution at this position abolishes TBK1 activity, whereas the phosphomimetic mutation S172E partially restores activity to within ∼200-fold of the wild-type kinase (20). Genetic and pharmacological inhibition studies have indicated that TBK1 can be activated by IKKβ, as well as by apparent autophosphorylation (10). Additional posttranslational modifications of TBK1 lysine residues by K63-linked polyubiquitin chains have been shown to promote production of IFNs in viral infections (21).TBK1 contains a predicted ubiquitin-like domain (ULD) (22) that is located between the N-terminal kinase domain (KD) and the C-terminal scaffolding/dimerization domain (SDD), a domain arrangement that appears to be shared among the IKK family of kinases (3). Deletion or mutation of the ULD in TBK1 or IKKε severely impairs kinase activation and substrate phosphorylation in cells (22,23). Furthermore, the integrity of the ULD in IKKβ is not only required for kinase activity (24) bu...

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“…Both pathways converge in the activation of the IκB kinase (IKK) complex and the IKK-related kinases TANK-binding kinase 1 (TBK1) and IKKε. The IKK complex, which includes the kinases IKKα and IKKβ as well as the regulatory subunit IKKγ/NEMO, is responsible for the activation of NF-κB, whereas TBK1 and IKKε phosphorylate and activate IRF3 and IRF7 [31,44,45]. In unstimulated cells, NF-κB, IRF3…”

Section: In Vitro Transcribed (Ivt) Mrnamentioning

confidence: 99%

Evading innate immunity in nonviral mRNA delivery: don’t shoot the messenger

Devoldere

Dewitte

Smedt

2016

Drug Discovery Today

113

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Teaser:This review presents an overview of the immune-related hurdles that limit mRNA advance for non-immunotherapy related applications and suggest some promising methods to reduce this 'unwanted' innate immune response. Author photographs and biographiesJoke Devoldere (1990) Her project lies on the interface between material science and immunology as it aims to develop novel micro-and nanomaterials for the delivery of antigen-coding mRNA to induce antitumor immunity. With her research, she won several awards, among which the "Therapeutic use of microbubbles" oral presentation award (Rotterdam, The Netherlands) and the Jan Feijen poster prize at the 13 th European symposium on controlled drug delivery (Egmond aan Zee, The Netherlands). Evading innate immunity in non-viral mRNA delivery: don't shoot the messenger AbstractIn de field of non-viral gene therapy, in vitro transcribed (IVT) mRNA has emerged as a promising tool for the delivery of genetic information. Over the past few years it has become widely known the introduction of IVT mRNA into mammalian cells elicits an innate immune response which has favored mRNA use towards immunotherapeutic vaccination strategies. However, for non-immunotherapy related applications this intrinsic immune-stimulatory activity directly interferes with the aimed therapeutic outcome, as it can seriously compromise the expression of the desired protein. This review presents an overview of the immune-related obstacles that limit mRNA advance for non-immunotherapy related applications.

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Involvement of the ubiquitin-like domain of TBK1/IKK-i kinases in regulation of IFN-inducible genes

Cited by 108 publications

References 45 publications

Are the IKKs and IKK-related kinases TBK1 and IKK-ɛ similarly activated?

Are the IKKs and IKK-related kinases TBK1 and IKK-ɛ similarly activated?

Molecular basis of Tank-binding kinase 1 activation by transautophosphorylation

Evading innate immunity in nonviral mRNA delivery: don’t shoot the messenger

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