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科学家揭示丙酮酸激酶M2的新功能
作者:小柯机器人 发布时间:2019/11/22 20:36:23

爱尔兰圣三一学院Luke A.J. O'Neill和Stefano Angiari合作的最新研究发现,通过药物激活丙酮酸激酶M2(PKM2)可以抑制CD4+ T细胞的致病性和抑制自身免疫。这一研究成果在线发表在11月21日的《细胞-代谢》杂志上。

研究人员发现在体外激活的小鼠和人CD4 + T细胞中会发生PKM2的上调、磷酸化和核内聚集。使用变构激活剂TEPP-46处理T细胞,可诱导PKM2四聚化并阻断其入核。通过抑制必需的信号通路可以显著降低PKM2的激活、增殖和细胞因子的产生,并最终阻止糖酵解作用。

TEPP-46限制了体外辅助性T细胞17(Th17)和Th1细胞的发育,并改善体内自身免疫性脑脊髓炎(EAE)。总而言之,该研究结果表明,PKM2可以作为T细胞介导的炎症和自身免疫的有效潜在药物靶点。

据介绍,丙酮酸激酶(PK)在糖酵解过程中催化磷酸烯醇丙酮酸生成丙酮酸。 PK同工酶PKM2在调节基因转录和蛋白质磷酸化方面具有其他作用。 已有研究表明PKM2可控制炎症中巨噬细胞的代谢重塑,但人们对其在T细胞中生物学作用了解甚少。

附:英文原文

Title: Pharmacological Activation of Pyruvate Kinase M2 Inhibits CD4+ T Cell Pathogenicity and Suppresses Autoimmunity

Author: Stefano Angiari, Marah C. Runtsch, Caroline E. Sutton, Eva M. Palsson-McDermott, Beth Kelly, Nisha Rana, Harry Kane, Gina Papadopoulou, Erika L. Pearce, Kingston H.G. Mills, Luke A.J. ONeill

Issue&Volume: November 21, 2019

Abstract: Pyruvate kinase (PK) catalyzes the conversion of phosphoenolpyruvate to pyruvate during glycolysis. The PK isoform PKM2 has additional roles in regulation of gene transcription and protein phosphorylation. PKM2 has been shown to control macrophage metabolic remodeling in inflammation, but its role in T cell biology is poorly understood. Here, we report PKM2 upregulation, phosphorylation, and nuclear accumulation in murine and human CD4+ T cells following activation in vitro. Treatment of T cells with TEPP-46, an allosteric activator that induces PKM2 tetramerization and blocks its nuclear translocation, strongly reduces their activation, proliferation, and cytokine production by inhibiting essential signaling pathways and thus preventing the engagement of glycolysis. TEPP-46 limits the development of both T helper 17 (Th17) and Th1 cells in vitro and ameliorates experimental autoimmune encephalomyelitis (EAE) in vivo. Overall, our results suggest that pharmacological targeting of PKM2 may represent a valuable therapeutic approach in T cell-mediated inflammation and autoimmunity.

DOI: 10.1016/j.cmet.2019.10.015

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(19)30606-0

期刊信息

Cell Metabolism:《细胞—代谢》,创刊于2005年。隶属于细胞出版社,最新IF:22.415
官方网址:https://www.cell.com/cell-metabolism/home
投稿链接:https://www.editorialmanager.com/cell-metabolism/default.aspx