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Structural studies of TBK1 reveal a dimeric assembly which is mediated by several interfaces involving the 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). IKKε forms homodimers upon co-expression of tagged monomers in human embryonic kidney 293 (HEK293) cells (Nakatsu Y et al., 2014). The ULDs of TBK1 and IKKε are involved in the control of kinase activation, substrate presentation, and downstream signaling (Ikeda F et al., 2007; Tu D et al., 2013). Upon activation, IKKε (IKBKE) is modified by K63-linked polyubiquitination on lysines 30 and 401 (Zhou AY et al. 2013). The ubiquitination sites and dimer contacts are conserved in IKKε and TBK1 (Tu D et al., 2013; Zhou AY et al., 2013). These findings suggest that both IKKε and TBK1 are regulated through similar activation mechanisms involving dimerization, phosphorylation, and ubiquitination. Activated IKKε (IKBKE) and TBK1 phosphorylate interferon (IFN) regulatory factor 3 (IRF3) and IRF7 leading to IFN production (Fitzgerald KA et al., 2003; Hemmi H et al., 2004; Hacker H & Karin M 2006; Taft J et al., 2021; Wegner J et al., 2023).
In this Reactome reaction, IKKε (IKBKE) is trans-autophosphorylated at S172 within the activated TLR3 complex.
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 TLR4 complex.
Toll-like receptor 4 and lymphocyte antigen 96 (LY96, also known as myeloid differentiation factor 2 (MD2)) form a heterodimer that specifically recognizes structurally diverse LPS molecules. A structural study of TLR4:LY96 complex revealed that LY96 (MD2) interaction with TLR4 relies on hydrogen and electrostatic bonds (Kim HM et al, 2007). LPS binds to the hydrophobic pocket of LY96 and directly mediates the dimerization of the two TLR4:LY96 complexes in a symmetrical manner. Both hydrophobic and hydrophilic interactions contribute to the main dimerization interaction between LY96, LPS and TLR4 multimer components. The phosphate groups of LPS also contribute to the receptor multimerization by forming ionic interactions with positively charged residues of TLR4 and LY96. (Park BS et al, 2009).
The activated TLR4 receptor is composed of two copies of the TLR4:LY96:LPS complex and initiates signal transduction by recruiting intracellular adaptor molecules.
HMGB1 can form immunostimulatory complexes with cytokines and other endogenous and exogenous ligands such as bacterial lipopolysaccharide (LPS) to potentiate proinflammatory response (Youn JH et al. 2008, 2011; Wähämaa H et al. 2011; Hreggvidsdottir HS et al. 2009). The activity of HMGB1 depended on the redox state of three cysteines at positions 23, 45 and 106 (C23, C45 and C106) (Urbonaviciute V et al. 2009; Venereau E et al. 2012, 2013; Yang H et al., 2013, 2021). Analysis revealed that the inflammatory activities of HMGB1 required both the formation of an intramolecular disulfide bond between C23 and C45 and the reduced state of C106 (thiol state, C106-SH) (Venereau E et al. 2012; Yang H et al. 2021).
HMGB1 binding to LPS facilitated transfer of LPS to CD14 and enhanced TNFalpha production in human peripheral blood mononuclear cells (PBMCs) (Youn JH et al. 2008). HMGB1 in complex with LPS boosted proinflammatory cytokine- and matrix metalloproteinase (MMP3) production in synovial fibroblasts obtained from rheumatoid arthritis (RA) and osteoarthritis (OA) patients (Wähämaa H et al. 2011; He ZW et al. 2013).
In addition to its ability to act in a synergy with LPS and other ligands, HMGB1 was shown to stimulate cells by direct interaction with innate immune receptors such as TLR4:LY96 (Yang H et al. 2010; Yang H et al. 2015).
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