1. Proprotein convertase FURIN constrains Th2 differentiation and is critical for host resistance against Toxoplasma gondii.
- Author
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Oksanen A, Aittomäki S, Jankovic D, Ortutay Z, Pulkkinen K, Hämäläinen S, Rokka A, Corthals GL, Watford WT, Junttila I, O'Shea JJ, and Pesu M
- Subjects
- Actins metabolism, Cell Differentiation, Cytokines metabolism, Furin genetics, GTPase-Activating Proteins, Guanine Nucleotide Exchange Factors metabolism, Humans, Immune Tolerance genetics, Immunity, Jurkat Cells, Protein Binding, STAT4 Transcription Factor metabolism, STAT6 Transcription Factor metabolism, Signal Transduction, rac1 GTP-Binding Protein metabolism, Furin metabolism, Th1 Cells immunology, Th2 Cells immunology, Toxoplasma immunology, Toxoplasmosis immunology
- Abstract
The proprotein convertase subtilisin/kexin enzymes proteolytically convert immature proproteins into bioactive molecules, and thereby they serve as key regulators of cellular homeostasis. The archetype proprotein convertase subtilisin/kexin, FURIN, is a direct target gene of the IL-12/STAT4 pathway and it is upregulated in Th1 cells. We have previously demonstrated that FURIN expression in T cells critically regulates the maintenance of peripheral immune tolerance and the functional maturation of pro-TGF-β1 in vivo, but FURIN's role in cell-mediated immunity and Th polarization has remained elusive. In this article, we show that T cell-expressed FURIN is essential for host resistance against a prototypic Th1 pathogen, Toxoplasma gondii, and for the generation of pathogen-specific Th1 lymphocytes, including Th1-IL-10 cells. FURIN-deficient Th cells instead show elevated expression of IL-4R subunit α on cell surface, sensitized IL-4/STAT6 signaling, and a propensity to polarize toward the Th2 phenotype. By exploring FURIN-interacting proteins in Jurkat T cells with Strep-Tag purification and mass spectrometry, we further identify an association with a cytoskeleton modifying Ras-related C3 botulinum toxin substrate/dedicator of cytokinesis 2 protein complex and unravel that FURIN promotes F-actin polymerization, which has previously been shown to downregulate IL-4R subunit α cell surface expression and promote Th1 responses. In conclusion, our results demonstrate that in addition to peripheral immune tolerance, T cell-expressed FURIN is also a central regulator of cell-mediated immunity and Th1/2 cell balance., (Copyright © 2014 by The American Association of Immunologists, Inc.)
- Published
- 2014
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