1. Proprotein Convertase FURIN Constrains Th2 Differentiation and Is Critical for Host Resistance against Toxoplasma gondii.
- Author
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Oksanen, Anna, Aittomäki, Saara, Jankovic, Dragana, Ortutay, Zsuzsanna, Pulkkinen, Kati, Hämäläinen, Sanna, Rokka, Anne, Corthals, Garry L., Watford, Wendy T., Junttila, Ilkka, O'Shea, John J., and Pesu, Marko
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TOXOPLASMA gondii , *PROPROTEIN convertases , *SUBTILISINS , *T cells , *LYMPHOCYTES , *CELL membranes , *CYTOKINESIS , *POLYMERIZATION - 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-ß1 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 a 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 a 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. [ABSTRACT FROM AUTHOR]
- Published
- 2014
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