IL-7 promotes Glut1 trafficking and glucose uptake via STAT5-mediated activation of Akt to support T-cell survival
IL-7 promotes Glut1 trafficking and glucose uptake via STAT5-mediated activation of Akt to support T-cell survival
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DOI：
10.1182/blood-2007-06-096297
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发表时间：
2008-02-15
期刊：
影响因子：
20.3
通讯作者：
Rathmell, Jeffrey C.
中科院分区：
文献类型：
--
作者：
Wofford, Jessica A.;Wieman, Heather L.;Rathmell, Jeffrey C.
淋巴细胞稳态需要协调代谢过程与细胞能量和生物合成需求，但调节T细胞代谢的机制尚不确定。我们发现白细胞介素-7（IL-7）是T淋巴细胞葡萄糖摄取的关键调节因子。为了确定IL-7如何影响葡萄糖摄取，我们分析了IL-7信号转导机制和葡萄糖转运蛋白Glut 1的调节。IL-7受体（IL-7 R）以需要IL-7 R Y 449的方式刺激葡萄糖摄取和Glut 1的细胞表面定位，其促进快速信号转导子和转录激活子5（STAT 5）活化和Akt的延迟但持续的活化。每种途径都是IL-7促进葡萄糖摄取所必需的，因为Akt 1（-/-）T细胞或PI 3-激酶抑制和STAT 5的RNAi导致响应于IL-7的葡萄糖摄取缺陷。STAT 5和Akt以线性途径起作用，STAT 5介导的转录导致Akt活化，这是STAT 5和IL-7促进葡萄糖摄取和防止细胞死亡所必需的。重要的是，IL-7需要葡萄糖摄取来促进细胞存活。这些数据表明，IL-7通过一种新的信号传导机制促进葡萄糖摄取，其中STAT 5转录活性促进Akt活化以调节Glut 1运输和葡萄糖摄取，这对于IL-7防止T细胞死亡和维持稳态至关重要。
Lymphocyte homeostasis requires coordination of metabolic processes with cellular energetic and biosynthetic demands but mechanisms that regulate T-cell metabolism are uncertain. We show that interleukin-7 (IL-7) is a key regulator of glucose uptake in T lymphocytes. To determine how IL-7 affects glucose uptake, we analyzed IL-7 signaling mechanisms and regulation of the glucose transporter, Glut1. The IL-7 receptor (IL-7R) stimulated glucose uptake and cell-surface localization of Glut1 in a manner that required IL-7R Y449, which promoted rapid signal transducer and activator of transcription 5 (STAT5) activation and a delayed yet sustained activation of Akt. Each pathway was necessary for IL-7 to promote glucose uptake, as Akt1(-/-) T cells or PI3-kinase inhibition and RNAi of STAT5 led to defective glucose uptake in response to IL-7. STAT5 and Akt acted in a linear pathway, with STAT5-mediated transcription leading to Akt activation, which was necessary for STAT5 and IL-7 to promote glucose uptake and prevent cell death. Importantly, IL-7 required glucose uptake to promote cell survival. These data demonstrate that IL-7 promotes glucose uptake via a novel signaling mechanism in which STAT5 transcriptional activity promotes Akt activation to regulate Glut1 trafficking and glucose uptake that is critical for IL-7 to prevent T-cell death and maintain homeostasis.