The peptidyl-prolyl isomerase Pin1 facilitates cytokine-induced survival of eosinophils by suppressing Bax activation

The mechanisms through which cytokine signals prevent the activation and mitochondrial targeting of the pro-apoptotic Bcl-2-associated X protein (Bax) are unclear. Here we showed, using primary human eosinophils, that in the absence of the pro-survival cytokines granulocyte macrophage-colony stimulating factor (GM-CSF) or interleukin 5, Bax spontaneously undergoes activation and initiates mitochondrial disruption. Bax inhibition reduced eosinophil apoptosis, even in the absence of cytokines. GM-CSF induced activation of Erk1/2, which phosphorylated Thr167 of Bax, which facilitated de novo interaction of Bax with the prolyl isomerase Pin1. Pin1 blockade led to Bax cleavage, mitochondrial translocation and caspase activation, irrespective of the presence of cytokines. Our findings indicate that Pin1 is a key mediator of pro-survival signaling and a regulator of Bax function.