Glycation & the RAGE axis: targeting signal transduction through DIAPH1

Abstract

The consequences of chronic disease are vast and unremitting; hence, understanding the pathogenic mechanisms mediating such disorders holds promise to identify therapeutics and diminish the consequences. The ligands of the receptor for advanced glycation end products (RAGE) accumulate in chronic diseases, particularly those characterized by inflammation and metabolic dysfunction. Although first discovered and reported as a receptor for advanced glycation end products (AGEs), the expansion of the repertoire of RAGE ligands implicates the receptor in diverse milieus, such as autoimmunity, chronic inflammation, obesity, diabetes, and neurodegeneration. Areas covered: This review summarizes current knowledge regarding the ligand families of RAGE and data from human subjects and animal models on the role of the RAGE axis in chronic diseases. The recent discovery that the cytoplasmic domain of RAGE binds to the formin homology 1 (FH1) domain, DIAPH1, and that this interaction is essential for RAGE ligand-stimulated signal transduction, is discussed. Finally, we review therapeutic opportunities targeting the RAGE axis as a means to mitigate chronic diseases. Expert commentary: With the aging of the population and the epidemic of cardiometabolic disease, therapeutic strategies to target molecular pathways that contribute to the sequelae of these chronic diseases are urgently needed. In this review, we propose that the ligand/RAGE axis and its signaling nexus is a key factor in the pathogenesis of chronic disease and that therapeutic interruption of this pathway may improve quality and duration of life.

Keywords: DIAPH1; Glycation; RAGE; diabetes; inflammation; neurodegeneration; obesity; receptor for AGE.

Figure 1

Model of S100B bound to two RAGE dimers showing the proposed interaction between RAGE cytoplasmic domains and FH1 domains of DIAPH1. Due to S100 ligation, the spacing between the RAGE cytoplasmic domains is comparable to the distance between the FH1 domains. The FH1 domains are unstructured; FH2 domains of DIAPH1 determine the distance between the FH1 domains. Reprinted and modified from Structure, 21/9, Xue et al., Change in the Molecular Dimension of a RAGE-Ligand Complex Triggers RAGE Signaling, 1509-1522, Copyright (2016), with permission from Elsevier.