LncRNA PVT1 links Myc to glycolytic metabolism upon CD4+ T cell activation and Sjögren's syndrome-like autoimmune response.,Journal of Autoimmunity

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LncRNA PVT1 links Myc to glycolytic metabolism upon CD4+ T cell activation and Sjögren's syndrome-like autoimmune response.
Journal of Autoimmunity ( IF 7.9 ) Pub Date : 2019-11-19 , DOI: 10.1016/j.jaut.2019.102358
Jiayao Fu ₁ , Huan Shi ₁ , Baoli Wang ₁ , Tianle Zhan ₁ , Yanxiong Shao ₁ , Lei Ye ₁ , Shufeng Wu ₁ , Chuangqi Yu ₁ , Lingyan Zheng ₁

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The hyperproliferation and hyperactivation of CD4+ T cells in salivary gland tissue is a hallmark of Sjögren's syndrome (SS). However, the role of long noncoding RNAs (lncRNAs) in the pathological process of SS and CD4+ T cell activation has not been fully elucidated. Here, we reported that lncRNA PVT1 was involved in the glycolytic metabolism reprogramming and proliferation upon CD4+ T cell activation. Expression of PVT1 was positively related with CD4+ T cell activation both in SS patients and Ex vivo antigen simulation. Depletion of PVT1 decreased the proliferation of murine CD4+ T cells and Jurkat T cells upon activation. We also showed that expression of the transcription factor Myc is regulated by PVT1 under antigen simulation. Depletion of PVT1 significantly decreased the expression of glycolytic genes, as well as several pivotal glycolytic proteins that were directly transcribed by Myc. Measurement of glucose content and lactate secretion indicated a defected lactate secretion and glucose uptake in PVT1-depleted T cells. Additionally, the real-time extracellular acidification rate (ECAR) and oxygen consumption rate (OCR) measurement also affirmed that PVT1 maintains glycolytic levels, glycolytic capacity under stress and ECAR/OCR ratios during T cell activation. Polarizing assays indicate that PVT1 depletion defected the function of Th1 effector cells as well as down-regulated Myc expression and glycolytic levels. Furthermore, we observed increased glycolytic levels in CD4+ T cells from SS-like NOD/Ltj mice. Treatment with 2-deoxy-d-glucose (2-DG), an inhibitor of glycolysis, significantly decreased the extent of lymphocyte infiltration and CD4+ T cell numbers and attenuated the defect of salivary flow in the lesioned submandibular glands of NOD/Ltj mice. Thus, our study demonstrated that lncRNA PVT1, which was upregulated in the CD4+T cells of SS patients, could maintain the expression of Myc, thus controlling the proliferation and effector functions of CD4+ T cells through regulating the reprogramming of glycolysis. Inhibition of glycolysis could attenuate the proliferation of CD4+ T cells and the SS-like autoimmune response. Our study provides a novel mechanistic function of lncRNA PVT1 in the pathogenesis of SS.

中文翻译：

LncRNA PVT1在CD4 + T细胞活化和Sjögren综合征样自身免疫反应后将Myc与糖酵解代谢联系起来。

唾液腺组织中CD4 + T细胞的过度增殖和过度活化是干燥综合征（SS）的标志。但是，尚未完全阐明长非编码RNA（lncRNA）在SS和CD4 + T细胞活化的病理过程中的作用。在这里，我们报道lncRNA PVT1参与CD4 + T细胞活化后的糖酵解代谢重编程和增殖。在SS患者和离体抗原模拟中，PVT1的表达与CD4 + T细胞活化呈正相关。激活后，PVT1的减少会降低鼠CD4 + T细胞和Jurkat T细胞的增殖。我们还显示，在抗原模拟下，转录因子Myc的表达受PVT1调控。PVT1的耗竭显着降低了糖酵解基因的表达，以及Myc直接转录的几种关键的糖酵解蛋白。葡萄糖含量和乳酸盐分泌的测量表明在缺乏PVT1的T细胞中乳酸盐分泌和葡萄糖摄取有缺陷。此外，实时细胞外酸化率（ECAR）和耗氧率（OCR）测量也证实，PVT1在T细胞活化过程中维持糖酵解水平，应激状态下的糖酵解能力和ECAR / OCR比。极化分析表明，PVT1耗竭缺陷Th1效应细胞的功能以及下调Myc表达和糖酵解水平。此外，我们观察到SS样NOD / Ltj小鼠的CD4 + T细胞糖酵解水平增加。用糖酵解抑制剂2-deoxy-d-glucose（2-DG）进行治疗，显着降低了NOD / Ltj小鼠病变下颌下腺的淋巴细胞浸润程度和CD4 + T细胞数量，并减轻了唾液流动缺陷。因此，我们的研究表明，在SS患者的CD4 + T细胞中上调的lncRNA PVT1可以维持Myc的表达，从而通过调节糖酵解的重新编程来控制CD4 + T细胞的增殖和效应子功能。抑制糖酵解可以减弱CD4 + T细胞的增殖和SS样自身免疫反应。我们的研究提供了lncRNA PVT1在SS发病机制中的新型机制功能。在SS患者CD4 + T细胞中上调的CD4 +可以维持Myc的表达，从而通过调节糖酵解的程序控制CD4 + T细胞的增殖和效应子功能。抑制糖酵解可以减弱CD4 + T细胞的增殖和SS样自身免疫反应。我们的研究提供了lncRNA PVT1在SS发病机制中的新型机制功能。在SS患者CD4 + T细胞中上调的CD4 +可以维持Myc的表达，从而通过调节糖酵解的程序控制CD4 + T细胞的增殖和效应子功能。抑制糖酵解可以减弱CD4 + T细胞的增殖和SS样自身免疫反应。我们的研究提供了lncRNA PVT1在SS发病机制中的新型机制功能。

更新日期：2019-11-20

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