DOC_TBK1_STING_1

The secretion of cytokines is a defence mechanism available to host cells when molecular sensors of its innate immune system detect the presence of pathogenic microorganisms or other unexpected molecules generated after tissue damage. These pathogen-associated molecular patterns (PAMPs) are recognized by pattern-recognition receptors (PRRs) such as IFN-β and other type I interferons (IFN) (Stetson,2006). The cyclic GMP-AMP synthase (cGAS) is one of the cytosolic PRRs. When cGAS senses the presence of viral DNA or other double-stranded DNA (dsDNA) in the cytosol, it subsequently synthesises cGAMP. This second messenger molecule promotes the translocation from the endoplasmic reticulum to the Golgi of the adaptor protein stimulator of interferon genes (STING) (Q86WV6; Sun,2013). The activated STING can then recruit and activate the TANK-binding kinase 1 (TBK1; Q9UHD2). Upon binding, TBK1 is activated and phosphorylates adjacent STING proteins in the S366 of a C-terminal motif instance from ELM class LIG_IRFs_LxIS_1 (27333035; 26235147). This ultimately leads to the activation of the transcription factor interferon regulatory factor 3 (IRF3), which induces the expression of interferon-stimulated genes responsible for the immune response.
The stimulator of interferon genes protein (STING) is typically linked to the endoplasmic reticulum membrane by the four helices in its transmembrane domain. A short loop connects to the C-terminal cytoplasmic ligand-binding and signalling domain. This cytoplasmic domain forms a domain-swapped dimer of STING molecules. Upon binding cGAMP, STING undergoes a conformational change that leads to the formation of STING tetramers with an adjacent STING dimer through side-by-side packing (30842659). These STING oligomers can then recruit TANK-binding kinase 1 (TBK1) through the C-terminal tail motif [DE]XPXPLR[ST]D (Zhang,2019; Zhao,2019). As mentioned, the oligomerization of STING initially involves the formation of tetramers, but these can further oligomerize, thus resulting in clusters of STING-bound TBK1 molecules (37086726). These clusters enable trans-autophosphorylation and mutual activation among the TBK1 molecules (3111851; Zhang,2019). cGAMP-bound STING oligomers translocate from the endoplasmic reticulum to a perinuclear compartment. This transition enhances the interaction between STING and TBK1 beyond their constitutive interaction levels in the absence of cGAMP.
The C-terminal tail of STING is well conserved among 60 species (Zhao,2019), including for example cows, boar, rats and bats. Experimental evidence of the motif-mediated interaction between STING and TBK1 is also conserved at the structural level, with similar motif arrangements and/or binding grooves observed in human (Zhao,2019), mouse (Zhao,2019) and chicken (Zhang,2019).
While preparing this entry, we noticed a strongly conserved match (residues 160-168) for IRAK2 to the motif in STING. IRAK2 (Interleukin receptor-associated kinase 2, O43187) is involved in innate immunity and inflammation, having for example, TRAF6-binding motifs (LIG_TRAF6_MATH_1). There appears to be no published direct connection of IRAK2 to TBK1, though their roles in innate immunity make them potential interactors. Therefore, we chose to include IRAK2 in the development of the motif, pending experimental testing.