TBK1 is phosphorylated within the activated TLR3 complex

Stable Identifier
R-HSA-9828205
Type
Reaction [transition]
Species
Homo sapiens
Related Species
Influenza A virus, Rotavirus, Hepatitis B virus, Hepatitis C Virus, Human herpesvirus 1
Compartment
endosome membrane, cytosol
Synonyms
TBK1 is phosphorylated within K63pUb-TANK:K63pUb-TRAF3:TICAM1:TLR3:viral dsRNA
ReviewStatus
5/5
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TBK1 is phosphorylated within the activated TLR3 complex
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TANK-binding kinase I (TBK1) and its close homolog inhibitor of kappaB kinase epsilon (IKKε or IKBKE) are serine/threonine protein kinases, that are activated by pattern-recognition receptors upon infection. Activity of both TBK1 and IKKε (IKBKE) is regulated by the phosphorylation of a serine residue 172 (S172) within the activation loop of the N-terminal kinase domain (KD) (Clark et al., 2009). The activation of TBK1 and IKKε may occur through autophosphorylation or via activity of a distinct protein kinase (Clark et al., 2009). Structural studies of TBK1 reveal a dimeric assembly which is mediated by several interfaces involving an N-terminal KD, a ubiquitin-like domain (ULD), and an alpha-helical scaffold dimerization domain (SDD) of TBK1 thus supporting a model of trans-autophosphorylation (Larabi A et al., 2013; Tu D et al., 2013). The ULD of TBK1 (and IKKε) is involved in the control of kinase activation, substrate presentation and downstream signaling (Ikeda F et al., 2007; Tu D et al., 2013). Upon activation, TBK1 is modified by K63-linked polyubiquitination on lysines 30 (K30) and K401 (Tu D et al., 2013). Ubiquitination of TBK1 leads to conformational changes that facilitate activation of the N-terminal KD while maintaining the overall dimer conformation (Larabi A et al., 2013). The ubiquitination and phosphorylation sites, as well as dimer contacts, are conserved in the close homolog IKKε (IKBKE) suggesting that both kinases are regulated through similar activation mechanisms (Tu D et al., 2013; Zhou AY et al., 2013). Activated TBK1 then phosphorylates IRF3 and IRF7.

TBK1, K63‑polyubiquitinated on K30 and K401, interacts with ubiquitin-binding adaptor protein optineurin (OPTN), which regulates the activity of TBK1 (Pourcelot M et al., 2016).

This Reactome event shows TBK1 phosphorylation within the activated TLR3 complex.

Literature References
PubMed ID Title Journal Year
15210742 The roles of two IkappaB kinase-related kinases in lipopolysaccharide and double stranded RNA signaling and viral infection

Takeuchi, O, Hoshino, K, Sanjo, H, Takeda, K, Sato, S, Yamamoto, M, Kaisho, T, Kawai, T, Hemmi, H

J Exp Med 2004
17047224 Regulation and function of IKK and IKK-related kinases

Karin, M, Hacker, H

Sci STKE 2006
27538435 The Golgi apparatus acts as a platform for TBK1 activation after viral RNA sensing

Arnoult, D, Vazquez, A, Pourcelot, M, Silva Da Costa, L, Zemirli, N, Loyant, R, Munitić, I, Garcin, D, Vitour, D

BMC Biol 2016
12692549 IKKepsilon and TBK1 are essential components of the IRF3 signaling pathway

Maniatis, T, Golenbock, DT, McWhirter, SM, Latz, E, Rowe, DC, Liao, SM, Fitzgerald, KA, Faia, KL, Coyle, AJ

Nat Immunol 2003
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
Participants
Input
Output
Participates
as an event of
This event is regulated
Positively by
Regulator
OPTN:TBK1:K63polyUb-TANK:K63polyUb-TRAF3:TRIF:activated TLR3 [endosome membrane] (Homo sapiens)
Active Unit
OPTN [cytosol]
Authored
Shamovsky, V  (2023-02-10)
Reviewed
Munitić, I  (2024-02-28)
Franjkić, T  (2024-02-28)
Created
Shamovsky, V  (2023-02-10)
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