Article abstract
Nature Immunology 10, 257 - 265 (2009)
Published online: 1 February 2009 | doi:10.1038/ni.1697
The peptidyl-prolyl isomerase Pin1 facilitates cytokine-induced survival of eosinophils by suppressing Bax activation
Zhong-Jian Shen1, Stephane Esnault1, Anna Schinzel2,3, Christoph Borner2 & James S Malter1
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.
- Waisman Center for Developmental Disabilities, the Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53705, USA.
- Institute of Molecular Medicine and Cell Research, Center for Biochemistry and Molecular Cell Research, Albert-Ludwigs-University Freiburg, D-79104 Freiburg, Germany.
- Present address: Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
Correspondence to: James S Malter1 e-mail: jsmalter@wisc.edu
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