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首页> 外文期刊>Journal of Leukocyte Biology: An Official Publication of the Reticuloendothelial Society >Proprotein convertase FURIN regulates T cell receptor-induced transactivation
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Proprotein convertase FURIN regulates T cell receptor-induced transactivation

机译：前蛋白转化酶FURIN调节T细胞受体诱导的反式激活

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摘要

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-beta 1 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-kappa B 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.
机译：抗原的出现会迅速刺激T细胞，从而导致细胞因子产生，细胞增殖和分化的改变。涉及这些事件的一些关键分子，例如TGF-beta 1和NOTCH1，最初是作为非活性前体合成的，并在T细胞活化过程中被蛋白水解活化。 PCSK通过催化其底物的蛋白水解切割来调节原蛋白的成熟。 PCSK FURIN原型在TCR激活后被诱导，其在T细胞中的表达对于维持外周免疫耐受至关重要。在这项研究中，我们测试了FURIN调节T细胞活化的假设。我们的数据表明IL-2最初增加了FURIN缺陷的小鼠CD4（+）T细胞中，但在缺少FURIN的情况下TCR诱导的IL-2 mRNA表达并没有持续。因此，在人Jurkat T细胞系中对FURIN的抑制也导致IL-2产生的减少，而WT FURIN的过表达与升高的IL-2水平有关。在Jurkat细胞中，对于立即的TCR信号传导步骤（例如ERK，ZAP70或LAT磷酸化），FURIN是不可或缺的。但是，通过使用基因报告基因检测，我们证明了FURIN调节AP-1，NFAT和NF-κB转录因子。最后，通过对FURIN依赖的转录组进行转录因子结合位点富集分析，我们确定了小鼠CD4（+）T细胞亚群中FURIN调控的转录因子。总的来说，我们的工作证实了以下假设：TCR调节的蛋白酶FURIN在T细胞活化中起重要作用，并且可以特异性调节TCR活化的反式激活。

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