The short isoform of PML-RARα activates the NRF2/HO-1 pathway through a direct interaction with NRF2.

The NF-E2 p45-related factor 2 (NRF2)-Kelch-like ECH-associated protein 1 signaling pathway plays an important role in cytoprotection. In acute promyelocytic leukemia, fusion of the promyelocytic leukemia protein (PML) with retinoic acid receptor alpha (RARα) results in an oncogene, PML-RARα (PR). Although previous studies have shown that both RARα and PML inhibit NRF2 activity, how PR regulates NRF2 has not been reported. Here, we discovered that PR-S, the short isoform of PR, potentiates NRF2 activity in a tert-butylhydroquinone (tBHQ) concentration-dependent manner. Furthermore, PR-S colocalized with NRF2 in HeLa and HEK293T cells. The association of PR-S and NRF2 is mediated by the DNA-binding domains of RARα and the Neh7 domain of NRF2. Our results define a novel function of PR-S as a NRF2-transcriptional co-activator.