Pan Fan, Sun Luo, Kardian David B, Whartenby Katharine A, Pardoll Drew M, Liu Jun O
Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Nature. 2007 Jan 25;445(7126):433-6. doi: 10.1038/nature05476. Epub 2007 Jan 17.
Feedback regulation of adaptive immunity is a fundamental mechanism for controlling the overall output of different signal transduction 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.
适应性免疫的反馈调节是控制不同信号转导途径整体输出的基本机制，包括由T细胞抗原受体（TCR）介导的途径。已知钙调神经磷酸酶和Ras在T细胞活化过程中具有重要功能。然而，在此过程中钙调神经磷酸酶信号通路是如何终止的仍很大程度上未知。尽管已报道了几种钙调神经磷酸酶的内源性抑制剂，但没有一种符合反馈抑制剂的标准，因为它们的表达对TCR信号不响应。在这里，我们鉴定了一种钙调神经磷酸酶的内源性抑制剂，名为Carabin，它还通过其内在的Ras GTP酶激活蛋白（GAP）活性抑制Ras信号通路。Carabin的表达在TCR信号传导时以上调，这种上调方式对钙调神经磷酸酶抑制剂敏感，表明Carabin构成细胞内TCR信号通路负调节环的一部分。通过短干扰RNA敲低Carabin导致体外和体内抗原特异性T细胞产生白细胞介素-2显著增强。因此，Carabin是钙调神经磷酸酶信号通路的负反馈抑制剂，它还介导钙调神经磷酸酶和Ras之间的串扰。
