Interleukin-18 up-regulates amino acid transporters and facilitates amino acid-induced mTORC1 activation in natural killer cells
Interleukin-18 up-regulates amino acid transporters and facilitates amino acid-induced mTORC1 activation in natural killer cells
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DOI：
10.1074/jbc.ra118.005892
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发表时间：
2019-03-22
影响因子：
4.8
通讯作者：
Lee, Seung-Hwan
中科院分区：
文献类型：
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作者：
Almutairi, Saeedah Musaed;Ali, Alaa Kassim;Lee, Seung-Hwan
发生炎症时，自然杀伤 (NK) 细胞会发生代谢变化，以支持其效应功能和增殖的高能量需求。代谢变化通常伴随着营养转运蛋白表达的增加，导致营养吸收增加。在诱导NK细胞增殖的多种细胞因子中，白细胞介素（IL）-18促进NK细胞增殖的机制尚不完全清楚。在这里，我们证明 IL-18 是一种有效的细胞因子，可以独立于 mTORC1 途径增强氨基酸营养转运蛋白 CD98/LAT1 的表达，从而诱导与 NK 细胞增殖增加相关的显着代谢变化。值得注意的是，用亮氨酸处理 IL-18 刺激的 NK 细胞会激活代谢传感器 mTORC1，表明氨基酸转运蛋白的高表达诱导氨基酸驱动的 mTORC1 激活。抑制氨基酸转运蛋白 CD98/LAT1 可消除亮氨酸驱动的 mTORC1 激活并降低 NK 细胞效应功能。综上所述，我们的研究确定了 IL-18 在上调 NK 细胞营养转运蛋白方面的新作用，从而诱导代谢变化，包括氨基酸激活 mTORC1。
Upon inflammation, natural killer (NK) cells undergo metabolic changes to support their high energy demand for effector function and proliferation. The metabolic changes are usually accompanied by an increase in the expression of nutrient transporters, leading to increased nutrient uptake. Among various cytokines inducing NK cell proliferation, the mechanisms underlying the effect of interleukin (IL)-18 in promoting NK cell proliferation are not completely understood. Here, we demonstrate that IL-18 is a potent cytokine that can enhance the expression of the nutrient transporter CD98/LAT1 for amino acids independently of the mTORC1 pathway and thereby induce a dramatic metabolic change associated with increased proliferation of NK cells. Notably, treatment of IL-18-stimulated NK cells with leucine activates the metabolic sensor mTORC1, indicating that the high expression of amino acid transporters induces amino acid-driven mTORC1 activation. Inhibition of the amino acid transporter CD98/LAT1 abrogated the leucine-driven mTORC1 activation and reduced NK cell effector function. Taken together, our study identified a novel role of IL-18 in up-regulating nutrient transporters on NK cells and thereby inducing metabolic changes, including the mTORC1 activation by amino acids.