EGFR promotes the apoptosis of CD4(+) T lymphocytes through TBK1/Glut1 induced Warburg effect in sepsis.
EGFR promotes the apoptosis of CD4(+) T lymphocytes through TBK1/Glut1 induced Warburg effect in sepsis.
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脓毒症中EGFR通过TBK1/Glut1诱导的Warburg效应促进CD4 T淋巴细胞凋亡
DOI：
10.1016/j.jare.2022.04.010
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发表时间：
2023-02
影响因子：
10.7
通讯作者：
Tang, Jing
中科院分区：
文献类型：
--
作者：
Huang, Li;Zhang, Xuedi;Fan, Junyu;Liu, Xiaolei;Luo, Shuhua;Cao, Dianqing;Liu, Youtan;Xia, Zhengyuan;Zhong, Hanhui;Chen, Cuiping;Zhang, Liangqing;Liu, Zhifeng;Tang, Jing
EGFR帮助Glut1通过TBK1/Exo84/Rala转位到CD4+T细胞表面，以响应内毒素。葡萄糖通过EGFR/Glut1信号通路转运，并通过Warburg效应代谢为乳酸，为CD4+T细胞的活化提供能量。EGFR促进活化的CD4+T细胞通过细胞凋亡而死亡，从而导致脓毒症时细胞耗竭。EGFR抑制剂有效地缓解了脓毒症小鼠总CD4+T细胞和幼稚CD4+T细胞的下降。脓毒症患者外周血中EGFR和Glut1的表面表达及人外周血中CD4+T细胞的活化增加。脓毒症诱导的细胞凋亡导致淋巴细胞减少，包括CD4+T细胞的减少，从而有利于免疫抑制。尽管表皮生长因子受体(EGFR)抑制剂能显著提高脓毒症小鼠的存活率，但EGFR对脓毒症小鼠外周血中CD4+T细胞功能和代谢的影响尚不清楚。在有或没有EGFR激活的情况下，对脓毒症小鼠和患者的CD4+T细胞的凋亡、激活、Warburg代谢和葡萄糖转运蛋白1(Glut1)的表达进行了评估。EGFR通过Glut1促进CD4+T细胞的活化和凋亡，Glut1是控制T细胞糖酵解的关键酶。EGFR、Tabk1和Glut1形成一个复合体，促进Glut1从细胞质到细胞表面的转运。脓毒症患者外周血中EGFR和Glut1的膜表达水平及CD4+T细胞的活化水平均显著高于正常对照组。我们的研究表明，EGFR通过其下游的TBK1/Exo84/Rala蛋白系统调节Glut1转运到细胞表面，这是诱导Warburg效应以及随后的CD4+T淋巴细胞活化和凋亡的关键步骤，并可能最终影响免疫功能状态，导致脓毒症时免疫细胞耗竭。
EGFR helps Glut1 translocate to CD4+ T cells surface via the TBK1/Exo84/RalA in response to LPS. Glucose is transported by EGFR/Glut1 signal pathway and metabolized to lactate via the Warburg effect to supply energy for CD4+ T cells activation. EGFR promotes activated CD4+ T cells die via apoptosis which leading to cell depletion in sepsis. EGFR inhibitors effectively alleviated the decrease in total CD4+ and naïve CD4+ T cells in septic mice. The surface expression of EGFR and Glut1 and activation of human blood CD4+ T cells increased in septic patients. Sepsis-induced apoptosis leads to lymphopenia including the decrease of CD4+ T cells thus favoring immunosuppression. Although epidermal growth factor receptor (EGFR) inhibitors significantly improve the survival rate of septic mice, the effect of EGFR on the function and metabolism of CD4+ T cells in sepsis remained unknown. CD4+ T cells from septic mice and patients were assessed for apoptosis, activation, Warburg metabolism and glucose transporter 1 (Glut1) expression with or without the interference of EGFR activation. EGFR facilitates CD4+ T cell activation and apoptosis through Glut1, which is a key enzyme that controls glycolysis in T cells. EGFR, TANK binding kinase 1 (TBK1) and Glut1 form a complex to facilitate Glut1 transportation from cytoplasm to cell surface. Both the levels of membrane expression of EGFR and Glut1 and the activation levels of CD4+ T cells were significantly higher in patients with sepsis as compared with healthy subjects. Our data demonstrated that through its downstream TBK1/Exo84/RalA protein system, EGFR regulates Glut1 transporting to the cell surface, which is a key step for inducing the Warburg effect and the subsequent cellular activation and apoptosis of CD4+ T lymphocytes and may eventually affect the immune functional status, causing immune cell exhaustion in sepsis.
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影响因子：
64.5
作者：
Prentzell MT;Rehbein U;Cadena Sandoval M;De Meulemeester AS;Baumeister R;Brohée L;Berdel B;Bockwoldt M;Carroll B;Chowdhury SR;von Deimling A;Demetriades C;Figlia G;Genomics England Research Consortium;de Araujo MEG;Heberle AM;Heiland I;Holzwarth B;Huber LA;Jaworski J;Kedra M;Kern K;Kopach A;Korolchuk VI;van 't Land-Kuper I;Macias M;Nellist M;Palm W;Pusch S;Ramos Pittol JM;Reil M;Reintjes A;Reuter F;Sampson JR;Scheldeman C;Siekierska A;Stefan E;Teleman AA;Thomas LE;Torres-Quesada O;Trump S;West HD;de Witte P;Woltering S;Yordanov TE;Zmorzynska J;Opitz CA;Thedieck K
通讯作者：
Thedieck K
影响因子：
29
作者：
Pucino, Valentina;Certo, Michelangelo;Mauro, Claudio
通讯作者：
Mauro, Claudio
影响因子：
29
作者：
Macintyre AN;Gerriets VA;Nichols AG;Michalek RD;Rudolph MC;Deoliveira D;Anderson SM;Abel ED;Chen BJ;Hale LP;Rathmell JC
通讯作者：
Rathmell JC
影响因子：
64.5
作者：
Chien, Yuchen;Kim, Sungchan;White, Michael A.
通讯作者：
White, Michael A.
影响因子：
7.7
作者：
Chattopadhyay, Saurabh;Veleeparambil, Manoj;Sen, Ganes C.
通讯作者：
Sen, Ganes C.