The heavy ion-induced up-regulation of ZIP14 is mediated by the PKCNrf2 pathway.

Heavy ion irradiation (IR) creates complex DNA lesions, posing a significant biological risk during space exposure. Zinc, an essential trace element, plays a crucial role in DNA repair; however, the mechanisms that maintain zinc homeostasis following irradiation are not well understood. In the present study, human bronchial epithelial BEAS-2B cells irradiated with carbon ions and cultured under zinc-deficient conditions exhibited increased and persistent γ-H2AX foci when compared to cells grown in medium with normal zinc contents. Further investigation revealed that ZIP14, a member of the Zrt/Irt-like protein (ZIP) family, is involved in the cellular response to IR-induced DNA damage repair (DDR). The knockdown of ZIP14 significantly reduced the cells' capacity for DDR. Additionally, protein kinase C (PKC), which is known to be activated by radiation, was found to play a role in regulating ZIP14. Overexpressing or activating PKC enhanced ZIP14 expression, while silencing PKC significantly attenuated the induction of ZIP14 by IR. PKC likely affects ZIP14 through its phosphorylation of Nrf2, which facilitates the nuclear translocation and accumulation of the transcription factor. Luciferase reporter assays and chromatin immunoprecipitation (ChIP) analyses identified a binding site (-2221 bp to -2210 bp) for Nrf2 in the upstream regulatory region of SLC39A14, the gene encoding ZIP14. In conclusion, our results demonstrate that ZIP14, regulated by the PKCNrf2 pathway, plays an important role in adjusting zinc homeostasis in response to DNA damage caused by heavy ion IR.