LMP1-mediated glycolysis induces myeloid-derived suppressor cell expansion in nasopharyngeal carcinoma.
LMP1-mediated glycolysis induces myeloid-derived suppressor cell expansion in nasopharyngeal carcinoma.
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LMP1介导的糖酵解诱导鼻咽癌中骨髓源性抑制细胞的扩增
DOI：
10.1371/journal.ppat.1006503
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发表时间：
2017-07
期刊：
影响因子：
6.7
通讯作者：
Li J
中科院分区：
文献类型：
--
作者：
Cai TT;Ye SB;Liu YN;He J;Chen QY;Mai HQ;Zhang CX;Cui J;Zhang XS;Busson P;Zeng YX;Li J
骨髓源性抑制细胞（MDSC）在肿瘤微环境中扩增，包括EB病毒（EBV）相关的鼻咽癌（NPC）。NPC中MDSC扩增和EBV感染之间的联系尚不清楚。在这里，我们表明EB病毒潜伏膜蛋白1（LMP 1）通过促进恶性细胞中的线粒体外糖酵解来促进肿瘤微环境中的MDSC扩张，这是最初通过频繁、同时检测到丰富的LMP 1、葡萄糖转运蛋白1而提出的免疫逃逸的情况。（GLUT 1）和肿瘤切片中的CD 33 + MDSC。整个过程已在体外重建。LMP 1促进多种糖酵解基因的表达，包括GLUT 1。这种代谢重编程导致Nod样受体家族蛋白3（NLRP 3）炎性体、考克斯-2和P-p65的表达增加，并因此导致IL-1β、IL-6和GM-CSF的产生增加。最后，恶性细胞环境的这些变化导致增强的NPC衍生的MDSC诱导。一个关键步骤是LMP 1与GLUT 1的物理相互作用，通过阻断其K48-泛素化和p62依赖性自溶小体降解来稳定GLUT 1蛋白。这项工作表明，LMP 1介导的糖酵解通过NLRP 3炎性体、考克斯-2和P-p65信号通路调节IL-1β、IL-6和GM-CSF的产生，以增强肿瘤相关MDSC的扩增，从而导致NPC中的肿瘤免疫抑制。EB病毒（Epstein-Barr virus，EBV）致癌蛋白潜伏膜蛋白1（Latent membrane protein 1，LMP 1）在鼻咽癌患者中的表达存在差异，并与肿瘤发生和肿瘤免疫抑制有关，但LMP 1导致肿瘤免疫逃逸的分子机制尚不清楚。迄今为止的工作表明，肿瘤相关的髓源性抑制细胞（MDSC）的扩增是肿瘤免疫抑制的主要原因，如在NPC中发现的。在此，我们发现肿瘤LMP 1表达与NPC患者的葡萄糖转运蛋白1（GLUT 1）水平、CD 33 + MDSC数量和不利的生存期相关。基于我们的体外分析结果，LMP 1促进NPC细胞中GLUT 1依赖性糖酵解，导致Nod样受体家族蛋白3（NLRP 3）炎性体、考克斯-2和P-p65信号通路的激活，并随后增加IL-1β、IL-6和GM-CSF的产生。重要的是，LMP 1与GLUT 1相互作用，以p62依赖性方式破坏其K48连接的泛素化和自体溶酶体降解，并通过诱导p65活化上调GLUT 1 mRNA和蛋白水平，从而稳定GLUT 1蛋白。因此，我们确定GLUT 1依赖性糖酵解是肿瘤诱导的MDSC分化所必需的，并且该过程与LMP 1表达相关。基于我们的发现，LMP 1介导的糖酵解是参与控制肿瘤免疫抑制的关键过程，并直接有助于肿瘤发生。
Myeloid-derived suppressor cells (MDSCs) are expanded in tumor microenvironments, including that of Epstein–Barr virus (EBV)-associated nasopharyngeal carcinoma (NPC). The link between MDSC expansion and EBV infection in NPC is unclear. Here, we show that EBV latent membrane protein 1 (LMP1) promotes MDSC expansion in the tumor microenvironment by promoting extra-mitochondrial glycolysis in malignant cells, which is a scenario for immune escape initially suggested by the frequent, concomitant detection of abundant LMP1, glucose transporter 1 (GLUT1) and CD33+ MDSCs in tumor sections. The full process has been reconstituted in vitro. LMP1 promotes the expression of multiple glycolytic genes, including GLUT1. This metabolic reprogramming results in increased expression of the Nod-like receptor family protein 3 (NLRP3) inflammasome, COX-2 and P-p65 and, consequently, increased production of IL-1β, IL-6 and GM-CSF. Finally, these changes in the environment of malignant cells result in enhanced NPC-derived MDSC induction. One key step is the physical interaction of LMP1 with GLUT1 to stabilize the GLUT1 protein by blocking its K48-ubiquitination and p62-dependent autolysosomal degradation. This work indicates that LMP1-mediated glycolysis regulates IL-1β, IL-6 and GM-CSF production through the NLRP3 inflammasome, COX-2 and P-p65 signaling pathways to enhance tumor-associated MDSC expansion, which leads to tumor immunosuppression in NPC. The expression of the Epstein-Barr virus (EBV) oncogenic protein denoted latent membrane protein 1 (LMP1) varies in patients with NPC and is linked to tumorigenesis and tumor immunosuppression, but the molecular mechanism through which LMP1 leads to tumor immune escape remains unknown. Work to date suggests that the expansion of tumor-associated myeloid-derived suppressor cells (MDSCs) is the main cause of tumor immunosuppression such as that found in NPC. Here, we found that tumor LMP1 expression is correlated with glucose transporter 1 (GLUT1) levels, CD33+ MDSC number and unfavorable survival in patients with NPC. Based on the results of our in vitro analysis, LMP1 promotes GLUT1-dependent glycolysis in NPC cells, resulting in activation of the Nod-like receptor family protein 3 (NLRP3) inflammasome, COX-2 and P-p65 signaling pathways and subsequently increased IL-1β, IL-6 and GM-CSF production. Importantly, LMP1 interacts with GLUT1 to stabilize the GLUT1 protein by disrupting its K48-linked ubiquitination and autolysosomal degradation in a p62-dependent manner and up-regulating the GLUT1 mRNA and protein levels by inducing p65 activation. Therefore, we determined that GLUT1-dependent glycolysis is required for tumor-induced MDSC differentiation and that this process is associated with LMP1 expression. Based on our findings, LMP1-mediated glycolysis is a key process involved in controlling tumor immunosuppression and directly contributes to oncogenesis.
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影响因子：
6.4
作者：
Garg, Ankita;Spector, Stephen A.
通讯作者：
Spector, Stephen A.
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影响因子：
4
作者：
Choe M;Brusgard JL;Chumsri S;Bhandary L;Zhao XF;Lu S;Goloubeva OG;Polster BM;Fiskum GM;Girnun GD;Kim MS;Passaniti A
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影响因子：
7.3
作者：
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通讯作者：
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DOI：
10.4049/jimmunol.1000901
发表时间：
2010-08-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
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作者：
Lechner MG;Liebertz DJ;Epstein AL
通讯作者：
Epstein AL
DOI：
10.1073/pnas.1120542109
发表时间：
2012-02-14
影响因子：
11.1
作者：
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通讯作者：
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