Abstract

Reactive oxygen species (ROS) are generated by aerobic metabolism, and their deleterious effects are buffered by the cellular antioxidant response, which prevents oxidative stress. The nuclear factor erythroid 2-related factor 2 (NRF2) is a master transcriptional regulator of the antioxidant response. Basal levels of NRF2 are kept low by ubiquitin-dependent degradation of NRF2 by E3 ligases, including the Kelch-like ECH-associated protein 1 (KEAP1). Here, we show that the stability and function of NRF2 is regulated by the type I phosphatidylinositol phosphate kinase {gamma} (PIPKI{gamma}), which binds NRF2 and transfers its product phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) to NRF2. PtdIns(4,5)P2 binding recruits the small heat shock protein HSP27 to the complex. Silencing PIPKI{gamma} or HSP27 destabilizes NRF2, reduces expression of its target gene HO-1, and sensitizes cells to oxidative stress. These data demonstrate an unexpected role of phosphoinositides and HSP27 in regulating NRF2 and point to PIPKI{gamma} and HSP27 as drug targets to destabilize NRF2 in cancer. In briefPhosphoinositides are coupled to NRF2 by PIPKI{gamma}, and HSP27 is recruited and stabilizes NRF2, promoting stress-resistance.