PP2A-AMPKα-HSF1 axis regulates the metal-inducible expression of HSPs and ROS clearance

Metals such as cadmium and arsenic are ubiquitous toxicants that cause a variety of adverse health effects. Heat shock proteins (HSPs) response to metal-induced stress and protect cells from further damage. However, the intracellular signalling pathways responsible for activation of HSPs expression are not fully understood. Here, we demonstrate that protein phosphatase 2A (PP2A) regulates expression of HSP70 and HSP27 via dephosphorylation of an AMP-activated protein kinase alpha subunit (AMPK alpha) at Thr172. Dephosphotylated AMPKa phosphorylates heat shock factor 1 (HSF1) at Ser303, leading to significant transcriptional suppression of HSP70 and HSP27 in CdCl2- or NaAsO2-treated cells. Suppression of PP2A regulatory B56 delta subunit resulted in the sustained phosphorylation of AMPKa upon CdCl2 treatment, subsequent reduction in expression of HSP70 and HSP27, and thereby dramatic reduction of reactive oxygen species (ROS) clearance. We further revealed that PP2A B56 delta physically interacted with AMPKa., providing evidence that PP2A B56 delta-AMPK alpha-HSF1 signalling pathway participated in regulating the inducible expression of HSPs and ROS clearance. Taken together, we identified a novel PP2A-dependent signalling pathway involved in regulation of HSPs expression in response to metal stress. (C) 2014 Elsevier Inc. All rights reserved.