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Antigen emergence rapidly stimulates T cells, which leads to changes in cytokine production, cell proliferation, and differentiation. Some of the key molecules involved in these events, such as TGF-β1 and NOTCH1, are synthesized initially as inactive precursors and are proteolytically activated during T cell activation. PCSKs regulate proprotein maturation by catalyzing the proteolytic cleavage of their substrates. The prototype PCSK FURIN is induced upon TCR activation, and its expression in T cells is critical for the maintenance of peripheral immune tolerance. In this study, we tested the hypothesis that FURIN regulates T cell activation. Our data demonstrate that IL-2 is increased initially in FURIN-deficient mouse CD4(+) T cells, but the TCR-induced IL-2 mRNA expression is not sustained in the absence of FURIN. Accordingly, the inhibition of FURIN in human Jurkat T cell lines also results in a decrease in IL-2 production, whereas the overexpression of WT FURIN is associated with elevated IL-2 levels. In Jurkat cells, FURIN is dispensable for immediate TCR signaling steps, such as ERK, ZAP70, or LAT phosphorylation. However, with the use of gene reporter assays, we demonstrate that FURIN regulates the AP-1, NFAT, and NF-κB transcription factors. Finally, by performing a transcription factor-binding site enrichment analysis on FURIN-dependent transcriptomes, we identify the FURIN-regulated transcription factors in mouse CD4(+) T cell subsets. Collectively, our work confirms the hypothesis that the TCR-regulated protease FURIN plays an important role in T cell activation and that it can specifically modulate TCR-activated transactivation., (© Society for Leukocyte Biology.)

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.)

Background: Proprotein convertase subtilisin/kexin (PCSK) enzymes cleave proproteins into mature end products. Previously, MBTPS1 and PCSK9 have been shown to regulate cholesterol metabolism and LDL receptor recycling, whereas FURIN and PCSK5 have been suggested to inactivate lipases and regulate inflammation in atherosclerosis. Here, we systematically analyzed the expression of PCSKs and their targets in advanced atherosclerotic plaques., Methods and Results: Microarray and quantitative real-time PCR experiments showed that FURIN (42.86 median fold, p = 2.1e-8), but no other PCSK, is universally overexpressed in the plaques of different vascular regions. The mRNA expression screen of PCSK target proteins in plaques identified many known factors, but it also identified the significant upregulation of the previously overlooked furin-processed B cell activating cytokines APRIL (TNFSF13, 2.52 median fold, p = 3.0e-5) and BAFF (TNFSF13B, 2.97 median fold, p = 7.6e-6). The dysregulation of FURIN did not associate with its htSNPs or the previously reported regulatory SNP (-229, rs4932178) in the promoter. Immunohistochemistry experiments showed the upregulation of FURIN in the plaque lymphocytes and macrophages where it was co-expressed with BAFF/TNFSF13B and APRIL/TNFSF13., Conclusions: Our data unequivocally show that FURIN is the primary PCSK that is dysregulated in the immune cells of advanced human atherosclerotic plaques, which implies a role for this enzyme in plaque pathology. Therefore, drugs that inhibit FURIN in arteries may modulate the course of this disease., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)