Novel ARNT-mediated Regulatory Paradigm of AHR Signaling

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SUMMARY/ABSTRACT AHR is a cytoplasmic receptor that has affinity for numerous xenobiotic ligands, which include halogenated aromatic hydrocarbons such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), one of the most potent AHR activators, and AHR signaling mediates the detrimental effects of environmental contaminants on body tissues and organs. Ligand binding induces nuclear translocation of AHR and interaction with the AHR binding partner, aryl hydrocarbon receptor nuclear translocator (ARNT), allowing recognition of specific DNA enhancer sequences. More recently endogenous and natural AHR ligands, such as tryptophan metabolites and dietary compounds, have been identified. These ligands induce AHR-mediated immunomodulatory effects such as controlling normal T cell differentiation and immune tolerance. ARNT is expressed as two isoforms, isoform 1 and 3, which differ in only 15 amino acids present in isoform 1. Despite their sequence similarity, we have found that the ARNT isoforms appear to have opposing functions in AHR signaling. As such, through work funded by my parent R01 (ES025809), we find that ARNT activity is a function of both unique phosphorylation of isoform 1 and the given isoform ratio within a particular cell type, which in turn is important for regulating the magnitude/outcome of the AHR response. Moreover, these data suggest that by modulating the ARNT isoform ratio will allow for fine-tuning of an immune response to control inflammation and resolution. Thus, it is critical that my laboratory maintain consistency in the face of the ongoing pandemic in order to continue these cutting- edge investigative avenues that have potential for clinical translation to treat a wide range of environmentally linked immune disorders. Accordingly, this supplement application is to request a portion of salary lost during the past year of COVID shutdowns and quarantine protocols to help support my senior research scientist until new long-term funding is secured.