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The Peptidyl-Prolyl Isomerase Pin1 Regulates Granulocyte-Macrophage Colony-Stimulating Factor mRNA Stability in T Lymphocytes¹

Waisman Center for Developmental Disabilities, Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine, Madison, WI 53705

Cytokine production is associated with both the normal and pathologic inflammatory response to injury. Previous studies have shown that the immunosuppressants cyclosporin A or FK506, which interact with the peptidyl-propyl isomerases cyclophilin A and FK506-binding protein (FKBP12), respectively, block cytokine expression. A third member of the peptidyl-propyl isomerase family, Pin1 is expressed by immune and other cells. Pin1 has been implicated in cell cycle progression, is overexpressed in human tumors, and may rescue neurons from -associated degeneration. However, the role of Pin1 in the immune system remains largely unknown. In this study, we analyze the role of Pin1 in GM-CSF expression by human PBMC and CD4⁺ lymphocytes. We show that Pin1 isomerase activity is necessary for activation-dependent, GM-CSF mRNA stabilization, accumulation, and protein secretion, but not non-AU-rich elements containing cytokine mRNAs, including TGF-β and IL-4. Mechanistically, Pin1 mediated the association of the AU-rich element-binding protein, AUF1, with GM-CSF mRNA, which determined the rate of decay by the exosome.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health (Specialized Center of Research-Asthma-P50HL56396; to J.S.M.).

² S.E. and Z.-J.S. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. James S. Malter, Waisman Center for Developmental Disabilities, R509T, 1500 Highland Avenue, University of Wisconsin, Madison, WI 53705. E-mail address: jsmalter{at}facstaff.wisc.edu

⁴ Abbreviations used in this paper: CsA, cyclosporin A; FKBP12, FK506-binding protein; ARE, AU-rich element; [pNA], free p-nitroanilide; PPIase, peptidyl-propyl isomerase; qPCR, real-time PCR; TTP, tristetraprolin.

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