Different modulation of STING/TBK1/IRF3 signaling by advanced glycation end products

Abstract

Advanced glycation end products (AGEs) are a heterogeneous group of compounds that are non-enzymatically produced by reactions between carbonyl compounds and proteins. Many types of AGEs are produced according to the type or concentration of the reacting carbonyl compound. We have previously demonstrated that a glycolaldehyde-derived AGE suppresses stimulator of interferon gene (STING)/TANK-binding kinase 1 (TBK1)/interferon regulatory transcription factor 3 (IRF3), which is a component of the innate immune system. In this report, we investigated the effects of AGEs prepared by several carbonyl compounds on STING/TBK1/IRF3 signaling. AGEs used in the present study were numbered based on the carbonyl compound type: AGE1, derived from glucose; AGE2, derived from glyceraldehyde; AGE3, derived from glycolaldehyde; AGE4, derived from methylglyoxal; and AGE5, derived from glyoxal. AGEs derived from aldehyde (AGE2 and AGE3) and dicarbonyl compounds (AGE4 and AGE5) suppressed cyclic GMP-AMP (cGAMP)-induced activation of STING/TBK1/IRF3 signaling, with different suppression efficiencies observed. Lysine modification by carbonyl compounds was related to the efficiency of the suppressive effect on STING/TBK1/IRF3 signaling. Among the AGEs used, only AGE1 enhanced cGAMP-induced activation of STING/TBK1/IRF3 signaling. Enhancing the modulation of STING/TBK1/IRF3 signaling by AGE1 was mediated by toll-like receptor 4. These results indicated that modulation of STING/TBK1/IRF3 signaling by prepared AGEs is dependent on the type and concentration of the carbonyl compound present. Modulating STING/TBK1/IRF3 signaling by AGEs may involve modification of lysine residues in proteins.

Keywords: Advanced glycation end products; Macrophage; Protein modification; STING/TBK1/IRF3 signaling.