The evolutionary process has conferred a dual - enzymatic and signaling - function on the ancestral metabolic enzyme indoleamine 2,3-dioxygenase 1 (IDO1), which has long been known for converting the essential amino acid tryptophan (TRP) into neuroactive and immunoactive catabolites (kynurenines). In addition to TRP catabolic activity, phosphorylated immunoreceptor tyrosine-based inhibitory motifs, present in the IDO1 protein, act as docking sites for different molecular partners, which activate positive (transcriptional) or negative (post-translational) modulation of IDO1 protein. The ligand-operated transcription factor aryl hydrocarbon receptor (AhR) contributes to Ido1 transcription, and it can be operated by both exogenous and endogenous ligands, including l-kynurenine itself, the first byproduct of TRP catabolism. Ligand-bound AhR is also a component of a ubiquitin ligase complex responsible for regulatory proteolysis of different target proteins. Because IDO1 half-life is controlled by the ubiquitin-proteasome system, we here discuss the possibility that AhR, in addition to enhancing Ido1 transcription, contributes to IDO1 regulation by a non-genomic mechanism affecting the protein's half-life.
Keywords: AhR; IDO1; ITIM; dendritic cells; immunoregulation; l-kynurenine; tryptophan metabolism; ubiquitin ligase complex.