Reactome | TBK1 is ubiquitinated within TBK1:K63polyUb-TANK:K63polyUb-TRAF3:TRIF:activated TLR4

TBK1 is ubiquitinated within TBK1:K63polyUb-TANK:K63polyUb-TRAF3:TRIF:activated TLR4

Stable Identifier

R-HSA-9823904

Type

Reaction [omitted]

Species

Homo sapiens

Compartment

endosome membrane, cytosol

ReviewStatus

5/5

Locations in the PathwayBrowser

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Immune System (Homo sapiens)

- Innate Immune System (Homo sapiens)
  - Toll-like Receptor Cascades (Homo sapiens)
    - Toll Like Receptor 4 (TLR4) Cascade (Homo sapiens)
      - MyD88-independent TLR4 cascade (Homo sapiens)
        
        TRIF (TICAM1)-mediated TLR4 signaling (Homo sapiens)
        
        Activation of IRF3, IRF7 mediated by TBK1, IKKε (IKBKE) (Homo sapiens)
        
        Regulation of TBK1, IKKε (IKBKE)-mediated activation of IRF3, IRF7 (Homo sapiens)
        
        TBK1 is ubiquitinated within TBK1:K63polyUb-TANK:K63polyUb-TRAF3:TRIF:activated TLR4 (Homo sapiens)

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TBK1 is ubiquitinated within TBK1:K63polyUb-TANK:K63polyUb-TRAF3:TRIF:activated TLR4

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Pathogen‑associated inflammatory signaling pathways result in activation of TANK‑binding kinase 1 (TBK1) and its close homolog inhibitor of kappaB kinase epsilon (IKKε , IKBKE). Activated TBK1 and IKKε (IKBKE) induce type I interferon production and modulate nuclear factor kappa‑B (NF‑kappa‑B) signaling (Fitzgerald KA et al., 2003; Hemmi H et al., 2004; Taft J et al., 2021; Wegner J et al., 2023). Structural studies of TBK1 reveal a dimeric assembly that is mediated by several interfaces involving an N-terminal kinase domain (KD), an ubiquitin‑like domain (ULD), and an alpha‑helical scaffold dimerization domain (SDD) of TBK1 (Larabi A et al., 2013; Tu D et al., 2013). The ULD of TBK1 (and IKBKE) is involved in the control of kinase activation, substrate presentation, and downstream signaling (Ikeda F et al., 2007; Tu D et al., 2013). TBK1 dimer is a subject to K63‑linked polyubiquitination on lysines 30 (K30) and 401 (K401) (Tu D et al., 2013). Activation of TBK1 rearranges the N-terminal KD into an active conformation while maintaining the overall dimer conformation (Larabi A et al., 2013). The E3 Ub ligases that ubiquitinate TBK1 at K30 and K401 in response to various stimuli are reviewed by Runde AP et al. (2022).

This Reactome reaction shows the ubiquitination of TBK1 at K30 and K401 within the activated TLR4 complex.

Literature References

PubMed ID	Title	Journal	Year
17599067	Involvement of the ubiquitin-like domain of TBK1/IKK-i kinases in regulation of IFN-inducible genes Dötsch, V, Rozenknop, A, Rogov, V, Nordmeier, RD, Ikeda, F, Akira, S, Dikic, I, Hecker, CM, Hofmann, K	EMBO J	2007
23453969	IKKε-mediated tumorigenesis requires K63-linked polyubiquitination by a cIAP1/cIAP2/TRAF2 E3 ubiquitin ligase complex Shen, RR, Hahn, WC, Chen, ZJ, Xu, M, Lock, YJ, Zhou, AY, Kim, E	Cell Rep	2013
23453971	Crystal structure and mechanism of activation of TANK-binding kinase 1 Devos, JM, Nanao, MH, Ng, SL, Round, A, Larabi, A, Panne, D, Maniatis, T	Cell Rep	2013
23453972	Structure and ubiquitination-dependent activation of TANK-binding kinase 1 Hahn, WC, Li, Y, Zhu, Z, Marto, JA, Lee, KE, Yun, CH, Jeon, H, Tu, D, Eck, MJ, Chan, E, Zhou, AY, Thai, T, Ficarro, SB, Dunn, GP, Barbie, DA, Yang, S, Toms, AV	Cell Rep	2013