P23 Co‐chaperone Protects Aryl Hydrocarbon Receptor (AHR) from the Autophagy‐Mediated Degradation

Abstract

The aryl hydrocarbon receptor (AHR) is first discovered as a transcription factor in response to toxic compounds such as dioxins. It also plays important roles in organ development, immune responses, metabolisms and carcinogenesis. Without ligand activation, AHR resides in the cytosol and is accompanied by Hsp90, p23 and XAP2. AHR is degraded via the 26S proteasome after ligand activation. However, it is still unclear how basal AHR protein levels are regulated. We previously discovered that AHR protein levels are lower in p23 stable knockdown (p23KD) cell lines when there is no ligand treatment. Here we report that treatment of proteasome inhibitor MG132 could not restore AHR in p23KD HeLa cells while the autophagy inhibitor chloroquine increased AHR proteins levels to 2.5 to 3‐fold in p23KD HeLa cells and 2‐fold in WT HeLa cells. Similar results were observed when cells were treated with other autophagy inhibitors (bafilomycin A1 and 3MA). There was higher autophagic flux in p23KD HeLa cells than in WT HeLa cells. Results from the co‐immunoprecipitation experiment and proximity ligation assay showed interaction between AHR and LC3B (LC3B‐II), which is an important protein in macroautophagy. These results support that the AHR protein levels are regulated by autophagy and p23 can protect AHR from the autophagy‐mediated degradation. Additional data will be presented to address the mechanisms of basal AHR protein degradation via autophagy.Support or Funding InformationNIH R15ES023104