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Feedback inhibition of calcineurin and Ras by a dual inhibitory protein Carabin

机译：双重抑制蛋白Carabin对钙调神经磷酸酶和Ras的反馈抑制

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摘要

Feedback regulation of adaptive immunity is a fundamental mechanism for controlling the overall output of different signal trans-duction pathways, including that mediated by the T-cell antigen receptor (TCR). Calcineurin and Ras are known to have essential functions during T-cell activation. However, how the calcineurin signalling pathway is terminated in the process is still largely unknown. Although several endogenous inhibitors of calcineurin have been reported, none fulfils the criteria of a feedback inhibitor, as their expression is not responsive to TCR signalling. Here we identify an endogenous inhibitor of calcineurin, named Carabin, which also inhibits the Ras signalling pathway through its intrinsic Ras GTPase-activating protein (GAP) activity. Expression of Carabin is upregulated on TCR signalling in a manner that is sensitive to inhibitors of calcineurin, indicating that Carabin constitutes part of a negative regulatory loop for the intracellular TCR signalling pathway. Knockdown of Carabin by short interfering RNA led to a significant enhancement of interleukin-2 production by antigen-specific T cells in vitro and in vivo. Thus, Carabin is a negative feedback inhibitor of the calcineurin signalling pathway that also mediates crosstalk between calcineurin and Ras.
机译：适应性免疫的反馈调节是控制不同信号转导途径（包括由T细胞抗原受体（TCR）介导的途径）的总体输出的基本机制。已知钙调神经磷酸酶和Ras在T细胞活化过程中具有基本功能。然而，钙调神经磷酸酶信号传导途径在该过程中如何终止仍是很大程度上未知的。尽管已报道了钙调神经磷酸酶的几种内源性抑制剂，但均未达到反馈抑制剂的标准，因为它们的表达对TCR信号无反应。在这里，我们确定了钙调神经磷酸酶的内源性抑制剂Carabin，它也通过其固有的Ras GTP酶激活蛋白（GAP）活性抑制了Ras信号通路。 Carabin的表达以对钙调神经磷酸酶抑制剂敏感的方式在TCR信号上调，表明Carabin构成了细胞内TCR信号通路负调节环的一部分。通过短干扰RNA抑制Carabin导致抗原特异性T细胞在体外和体内的白介素-2产量显着提高。因此，Carabin是钙调神经磷酸酶信号传导途径的负反馈抑制剂，它也介导钙调神经磷酸酶与Ras之间的串扰。

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