The peptidyl-prolyl isomerase Pin1 facilitates cytokine-induced survival of eosinophils by suppressing Bax activation.
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.
Shen
Zhong-Jian
ZJ
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.
Esnault
Stephane
S
Schinzel
Anna
A
Borner
Christoph
C
Malter
James S
JS
D016923:Cell Death; D002470:Cell Survival; D002478:Cells, Cultured; D004804:Eosinophils / Q000276:immunology* / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000276:immunology / Q000378:metabolism; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D015848:Interleukin-5 / Q000276:immunology* / Q000378:metabolism; D008928:Mitochondria / Q000276:immunology / Q000378:metabolism; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D019696:Peptidylprolyl Isomerase / Q000276:immunology* / Q000378:metabolism; D010766:Phosphorylation; D021381:Protein Transport; D051028:bcl-2-Associated X Protein / Q000276:immunology* / Q000378:metabolism
C508599:IL5 protein, human; D015848:Interleukin-5; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D051028:bcl-2-Associated X Protein; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D048049:Extracellular Signal-Regulated MAP Kinases; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase