Evidence for crosstalk between the aryl hydrocarbon receptor and the translocator protein in mouse lung epithelial cells

Cellular homeostasis requires the use of multiple environmental sensors that can respond to a variety of endogenous and exogenous compounds. The aryl hydrocarbon receptor (AHR) is classically known as a transcription factor that induces genes that encode drug metabolizing enzymes when bound to toxicants such as 2,3,7,8-tetrachlorodibenzo-?-dioxin (TCDD). The receptor has a growing number of putative endogenous ligands, such as tryptophan, cholesterol, and heme metabolites. Many of these compounds are also linked to the translocator protein (TSPO), an outer mitochondrial membrane protein. Given a portion of the cellular pool of the AHR has also been localized to mitochondria and the overlap in putative ligands, we tested the hypothesis that crosstalk exists between the two proteins. CRISPR/Cas9 was used to create knockouts for AHR and TSPO in a mouse lung epithelial cell line (MLE-12). WT, AHR-/-, and TSPO-/- cells were then exposed to AHR ligand (TCDD), TSPO ligand (PK11195), or both and RNA-seq was performed. More mitochondrial-related genes were altered by loss of both AHR and TSPO than would have been expected just by chance. Some of the genes altered included those that encode for components of the electron transport system and the mitochondrial calcium uniporter. Both proteins altered the activity of the other as AHR loss caused the increase of TSPO at both the mRNA and protein level and loss of TSPO significantly increased the expression of classic AHR battery genes after TCDD treatment. This research provides evidence that AHR and TSPO participate in similar pathways that contribute to mitochondrial homeostasis.

Automated summary

Cellular homeostasis requires the use of multiple environmental sensors to respond to different compounds. The aryl hydrocarbon receptor (AHR) and the translocator protein (TSPO) are two proteins involved in cellular homeostasis, and their interaction affects mitochondrial-related genes. Knockouts for AHR and TSPO were created in a mouse lung epithelial cell line, and the cells' response to ligands for AHR and TSPO was analyzed through RNA-seq. The results suggest that AHR and TSPO participate in similar pathways that contribute to mitochondrial homeostasis.