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

Abstract

The mechanisms by which cytokine signals prevent the activation and mitochondrial targeting of the proapoptotic protein Bax are unclear. Here we show, using primary human eosinophils, that in the absence of the prosurvival cytokines granulocyte-macrophage colony-stimulating factor and interleukin 5, Bax spontaneously underwent activation and initiated mitochondrial disruption. Inhibition of Bax resulted in less eosinophil apoptosis, even in the absence of cytokines. Granulocyte-macrophage colony-stimulating factor induced activation of the kinase Erk1/2, which phosphorylated Thr167 of Bax; this facilitated new interaction of Bax with the prolyl isomerase Pin1. Blockade of Pin1 led to cleavage and mitochondrial translocation of Bax and caspase activation, regardless of the presence of cytokines. Our findings indicate that Pin1 is a key mediator of prosurvival signaling and is a regulator of Bax function.

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Figure 1: Blockade of Pin1 suppresses cytokine-induced survival.
Figure 2: Pin1 interacts with Bax and regulates its activation.
Figure 3: Blockade of Pin1 causes mitochondrial translocation of Bax.
Figure 4: Phosphorylation of Bax Thr167 facilitates cell survival.
Figure 5: Bax associates with and is phosphorylated by Erk1/2.
Figure 6: The activity and cleavage of Bax are modified by calpain inhibitors and cytokine signaling.

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Acknowledgements

We thank J. Sedgwick () for eosinophils; K.P. Lu (Harvard University) for the Pin1 WW domain cDNA; N. Jarjour (University of Wisconsin) for bronchoscopy samples; S. Dowdy (Washington University) for pHisTAT; and members of the lab and the University of Wisconsin Asthma Working Group for suggestions. Supported by the National Institutes of Health (R01HL087950, P01HL088594 and P30HD03352 to J.S.M.), the Jose Carreras Leukemia Foundation of Germany (C.B.), Deutsche Forschungsgesellschaft (GRK1004, Graduate School GSC-4 and Excellence Cluster Centre for Biological Signalling Studies; C.B.) and Bundesministerium für Bildung und Forschung (HepatoSys; C.B.) and the Swiss National Science Foundation (A.S.).

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Z.-J.S. designed and did most experiments and wrote the initial manuscript; S.E. designed and did several experiments and provided key reagents; A.S. provided several key reagents; C.B. helped to write and edit the manuscript; and J.S.M. conceived the project, helped to design the experiments and wrote and edited the manuscript.

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Correspondence to James S Malter.

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Shen, ZJ., Esnault, S., Schinzel, A. et al. The peptidyl-prolyl isomerase Pin1 facilitates cytokine-induced survival of eosinophils by suppressing Bax activation. Nat Immunol 10, 257–265 (2009). https://doi.org/10.1038/ni.1697

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