WDR23 regulates the expression of Nrf2-driven drug-metabolizing enzymes.

Nrf2 plays a central role in the response to xenobiotics and oxidative stress. The activation of Nrf2 induces the expression of drug-metabolizing enzymes (DMEs) and is important for cytoprotection. Keap1 is a widely accepted proteasome-dependent regulator of Nrf2. Keap1 was reported to be absent in Caenorhabditis elegans, and the level of the Nrf2 ortholog SKN-1 was mainly regulated by WDR23. The WDR23 locus is highly conserved from C. elegans to humans. We investigated whether WDR23 regulates Nrf2 activity in mammalian cells, hepatocellular carcinoma cells (Hep3B) and human cervical carcinoma cells (HeLa). We found that WDR23 has two isoforms (1 and 2) and that knockdown of WDR23 was sufficient to stabilize Nrf2 and alter the expression of several DMEs. Keap1 knockdown resulted in higher Nrf2 levels than WDR23 knockdown, and their effects on DMEs differed. These results were consistent with Keap1 being a canonical regulator of Nrf2, and that WDR23 may assist in Nrf2 regulation. We confirmed that WDR23 physically interacted with Nrf2, suggesting that WDR23 directly regulates Nrf2-dependent DMEs. In immunostaining experiments, human WDR23 isoform 1 was localized to the cytoplasm, whereas isoform 2 mainly resided in the nucleus. Taken together, our results suggested WDR23 is a novel regulator of DME expression.

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