Fig. 6: PHKG2 promotes NRF2 nuclear export by disrupting PPP1R3B–PP1C interactions. | Cell Death & Disease

Fig. 6: PHKG2 promotes NRF2 nuclear export by disrupting PPP1R3B–PP1C interactions.

From: Transcriptional activation of PHKG2 by TP53 promotes ferroptosis through nuclear export of NRF2 in head and neck squamous cell carcinoma

Fig. 6

Phosphorylation prediction analysis indicated PHKG2 phosphorylation of PPP1R3B at Ser64 within the RVXF motif, essential for interaction with PP1C (A). Western blotting showed that PHKG2 knockdown elevated p-GSK3β (Ser9) and nuclear NRF2 levels, without altering total GSK3β or NRF2 protein levels (B). Co-IP assays confirmed direct interactions of PPP1R3B with PP1C and PHKG2, influenced by PHKG2 expression levels (C, D). Immunoprecipitation revealed reduced PPP1R3B phosphorylation upon PHKG2 knockdown (E). Western blot experiments showed that the PP1 inhibitor Calyculin A and the nuclear export inhibitor Leptomycin B (LMB) increased nuclear NRF2 accumulation, whereas co-treatment showed no further synergism, suggesting PP1 primarily promotes NRF2 nuclear export (F). Additionally, nuclear import inhibition by SN50 failed to fully prevent NRF2 nuclear accumulation induced by Calyculin A, further supporting PP1’s role in nuclear export (G). The schematic illustrates the proposed mechanism: TP53-mediated PHKG2 activation triggers PPP1R3B phosphorylation, disrupting PPP1R3B–PP1C interactions, thereby enhancing PP1 activity, reducing nuclear NRF2 and GPX4 levels, decreasing intracellular GSH, and elevating ROS and Fe2+, ultimately promoting ferroptosis (**p < 0.01, ***p < 0.001) (H).

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