The peptidyl-prolyl isomerase Pin1 suppresses Bax activation and mitochondrial targeting in human eosinophils (139.7)

Abstract

Abstract Pulmonary eosinophilic inflammation is a defining feature of allergic asthma. Within a few days of allergen challenge, airway eosinophils (Eos) increase by ~20-fold in both human and animals. Genetic ablation of Eos markedly attenuates submucosal matrix deposition, airway smooth muscle hyperplasia as well as airway hyperresponsiveness, suggesting a critical role of these cells in asthmatic lung pathology. Normally short-lived (~3 days) peripheral blood Eos acquire prolonged survival (>7 days) in the lung by contacting with anti-apoptotic cytokines GM-CSF and IL-5, which increase after allergen exposure. How these cytokines suppress Eos apoptosis remains largely unknown. Here we show that Pin1 mediates GM-CSF/IL-5 signaling, inhibits activation of proapoptotic Bax and its mitochondrial disruption. Both cytokines considerably increased Pin1 isomerase activity while induced Erk1/2-mediated phosphorylation of Bax at Pin1 recognition sites, allowing Bax interaction with Pin1. Pin1 blockade disrupted this interaction, resulting in Bax N-terminal activation, mitochondrial translocation and downstream caspase 9 activation even in the presence of survival cytokines. Our study uncovers previously unknown mechanism by which Pin1 isomerization regulates Bax activation. Pin1 may be an attractive therapeutic target for the asthma and other eosinophilic diseases.