CGAs sting see nature again

Nucleic acids from bacteria or viruses can produce strong immune responses in the infected cells, and the detection of pathogen derived nucleic acids is the core strategy for the host to sense infection and initiate protective immune responses CGAs (cyclic GMP amp synthase) is a double stranded DNA sensor, which can catalyze the synthesis of cGMP (cyclic GMP amp) Cgamp, stimulated by sting-tbk1-irf-3 signal axis, induced the generation of type I interferon The oligomerization of sting and cgamp resulted in the recruitment and activation of tbk1 kinase IRF-3 transcription factors were then recruited into the signal complex and activated by tbk1 In the whole process, the activation of tbk1 is the key step of the activation of cgas-sting signaling pathway, but how tbk1 is recruited and the molecular mechanism of its activation are not clear In the process of exploring the function of sting mutant, researchers found that sting lost its vitality when nine amino acids at the C-terminal of sting were cut It was found that sting, which lost 9 amino acids of C-terminal, could not bind to tbk1 to play a corresponding biological role The experimental results of immunocoprecipitation confirmed once again that the truncated sting could not combine with tbk1 and mediate the corresponding biological function of downstream tbk1 (as shown in Figure 1) Fig 1 Sting inactivation (cutting C-terminal 9aa) After that, researchers expressed wild-type sting and several of its mutants, and mutated 9 amino acids of sting into alanine one by one It was found that - l374a point mutation would completely inactivate sting According to the IFN - β Luciferase Report, the researchers found that these mutations also affect the expression of interferon In order to eliminate the differences between species, the researchers analyzed the sting amino acid sequence of different species and found that the plplrt / SD sequence combined with tbk1 was very conservative To study how sting combines with tbk1, the researchers analyzed the crystal structure of sting C-terminal and tbk1 complex (as shown in Figure 2) The structure shows that the plplplrt / SD module of sting is combined on the surface of tbk1 According to the crystal structure, the researchers designed several mutants of tbk1 and prepared tbk1 knockout cells with crispr-cas9 technology The functional study of these mutants found that the mutation of the binding residue with sting would affect the activation of the signaling pathway downstream of sting The researchers also found that mutations in the binding region of tbk1-sting can also affect the downstream signaling pathway of sting to play a corresponding biological function Fig 2 Crystal structure of sting C-terminal and tbk1 complex To sum up, sting conservative motif plplrt / SD can mediate the recruitment and activation of tbk1, affect the generation process of type I interferon, and then affect its corresponding biological functions Figure 3 Article overview figure related products: bx795 is an effective, selective tbk1 / PDK1 dual inhibitor, IC50 value is 6 nm / 6 nm, and its selectivity is more than 50 times of PKA, PKC, c-kit, GSK3 β, etc Bx795 inhibited the phosphorylation of S6K1, Akt, PKC δ and GSK3 β Cgamp (cyclicgmp amp) is the second endogenous messenger in multicellular animals, which can stimulate the production of interferon, sting ligand and activator C-176 is a potent covalent inhibitor of interferon gene stimulating receptor (sting) H-151 is an efficient, selective and covalent sting antagonist, which can reduce the phosphorylation of tbk1 and inhibit the palmitoylation of human sting