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The peptidyl-prolyl isomerase Pin1 regulates the stability of granulocyte-macrophage colony-stimulating factor mRNA in activated eosinophils

Nature Immunology volume 6, pages 1280–1287 (2005)Cite this article

Abstract

The infiltration, accumulation and degranulation of eosinophils in the lung represents a hallmark of active asthma. In vivo or in vitro eosinophil activation triggers the secretion of the antiapoptotic cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF). We now identify Pin1, a cis-trans isomerase, as an essential component of the ribonucleoprotein complex responsible for GM-CSF mRNA stabilization, cytokine secretion and the survival of activated eosinophils. Pin1 regulated the association of the AU-rich element–binding proteins AUF1 and hnRNP C with GM-CSF mRNA, accelerating or slowing decay, respectively. These data indicate Pin1 is a key mediator of GM-CSF production.

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Figure 1: Pin1 is required for eosinophil survival.
Figure 2: Pin1 inhibition accelerates the decay of GM-CSF mRNA.
Figure 3: Pin1 associates with AUF1.
Figure 4: GM-CSF mRNA 'partitions' between AUF1 and hnRNP C.
Figure 5: Hyaluronic acid induces Pin1 dephosphorylation and isomerase activity.
Figure 6: The p37 isomer of AUF1 interacts with the exosome.
Figure 7: In vivo activation increases Pin1 activity and eosinophil survival and modulates GM-CSF mRNA–protein interactions.

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Acknowledgements

We thank J. Sedgwick for eosinophils; K.P. Lu (Harvard University, Boston, Massachusetts) for the Pin1 WW domain cDNA; N. Jarjour for bronchoscopy samples; P. Bertics for critical reading of the manuscript; and members of the lab and the UW-Asthma SCOR group for suggestions. Supported by the National Institutes of Health (P50HL56396 to J.S.M.).

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  1. Zhong-Jian Shen and Stephane Esnault: These authors contributed equally to this work.

Authors and Affiliations

  1. the Department of Pathology and Laboratory Medicine, The Waisman Center for Developmental Disabilities, University of Wisconsin School of Medicine, Madison, 53705, Wisconsin, USA

    Zhong-Jian Shen, Stephane Esnault & James S Malter

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Correspondence to James S Malter.

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Supplementary Table 1

Possible Pin1 targets in AREBPs. (PDF 29 kb)

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Shen, ZJ., Esnault, S. & Malter, J. The peptidyl-prolyl isomerase Pin1 regulates the stability of granulocyte-macrophage colony-stimulating factor mRNA in activated eosinophils. Nat Immunol 6, 1280–1287 (2005). https://doi.org/10.1038/ni1266

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