AhR-mediated, non-genomic modulation of IDO1 function

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 Idol transcription, and it can be operated by both exogenous and endogenous ligands, including ukynurenine 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 Idol transcription, contributes to IDO1 regulation by a non-genomic mechanism affecting the protein's half-life.