The aryl hydrocarbon receptor (AHR) is an important ligand-activated transcription factor that acts as an environmental sensor. Its ligands range from various environmental pollutants to tryptophan-derived metabolites such as kynurenine. Upon ligand binding, AHR induces the transcription of target genes and undergoes rapid degradation by the proteasome, although the E3 ligase responsible for targeting ligand-activated AHR for degradation has remained unknown.
Beyond its role in xenobiotic metabolism, AHR has recently been implicated in the regulation of antitumour immunity through crosstalk with the nuclear ADP-ribosyltransferase PARP7. However, the mechanisms underlying this interplay are poorly understood. To address this, we performed a CRISPR screen using a selective PARP7 inhibitor across a panel of lung cancer cell lines. We found that in all tested cell lines, AHR deletion or inactivation causes resistance to the PARP7 inhibitor. Conversely, simultaneous activation of AHR and inhibition of PARP7 leads to robust proteome remodelling and enhanced suppression of cancer cell growth. AHR levels decreased upon activation with a ligand, consistent with its known degradation mechanism, but PARP7 inhibition increased AHR levels.
Mechanistically, we found that PARP7 quantitatively ADP-ribosylates both itself and AHR, which leads to their rapid proteasomal degradation. We identified the E3 ligase that recognises the ADP-ribose mark on heavily ADP-ribosylated AHR and PARP7, ubiquitylating and targeting them for degradation. Thus, we establish a previously elusive mechanism to rapidly shut down AHR-mediated transcription.