Regulation of Phosphatidylinositol-5-Phosphate Signaling by Pin1 Determines Sensitivity to Oxidative Stress

Willem-Jan Keune¹, David R. Jones¹, Yvette Bultsma¹, Lilly Sommer¹, Xiao Zhen Zhou², Kun Ping Lu², and Nullin Divecha^1*

¹ CRUK Inositide Laboratory, Paterson Institute for Cancer Research (PICR), The University of Manchester, Manchester M20 4BX, UK.
² Department of Medicine, Beth Israel Deaconess Medical Centre, Harvard Medical School, Boston, MA 02215, USA.

Abstract: Oxidative signaling and oxidative stress contribute to aging, cancer, and diseases resulting from neurodegeneration. Pin1 is a proline isomerase that recognizes phosphorylated substrates and regulates the localization and conformation of its targets. Pin1^–/– mice show phenotypes associated with premature aging, yet mouse embryonic fibroblasts (MEFs) from these mice are resistant to hydrogen peroxide (H₂O₂)–induced cell death. We found that the abundance of phosphatidylinositol-5-phosphate (PtdIns5P) was increased in response to H₂O₂, an effect that was enhanced in Pin1^–/– MEFs. Reduction of H₂O₂-induced PtdIns5P compromised cell viability in response to oxidative stress, suggesting that PtdIns5P contributed to the enhanced cell viability of Pin1^–/– MEFs exposed to oxidative stress. The increased PtdIns5P in the Pin1^–/– MEFs stimulated the expression of genes involved in defense against oxidative stress and reduced the accumulation of reactive oxygen species. Pin1 and PtdIns5P 4-kinases (PIP4Ks), enzymes that phosphorylate and thereby reduce the amount of PtdIns5P, interacted in a manner dependent on the phosphorylation of PIP4K. Although reintroduction of Pin1 into the Pin1^–/– MEFs reduced the amount of PtdIns5P produced in response to H₂O₂, in vitro assays indicated that the isomerase activity of Pin1 inhibited PIP4K activity. Whether this isomerise-mediated inhibition of PIP4K occurs in cells remains an open question, but the data suggest that the regulation of PIP4K by Pin1 may be complex.

* To whom correspondence should be addressed. E-mail: ndivecha{at}picr.man.ac.uk

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