细胞骨架结构可调节糖酵解
2020-02-14   阅读:267   来源:自然

美国得克萨斯大学西南医学中心Gaudenz DanuserChristoph J. Burckhardt研究组合作,发现通过细胞骨架结构机械调节糖酵解。2020212日,《自然》在线发表了这项成果。

他们报道,人支气管上皮细胞从硬质基质向软质基质的转移,通过限速代谢酶磷酸果糖激酶(PFK)的蛋白酶体降解引起糖酵解的下调。PFK降解是由应力纤维的分解触发的,应力纤维的释放了靶向PFKE3泛素连接酶三重基序(TRIM),包括蛋白21TRIM21)。转化后的非小细胞肺癌细胞,无论环境机制如何变化,都能维持较高的糖酵解速率,并通过下调TRIM21并将螯合保留在对基质刚性不敏感的应力纤维亚区上残留的TRIM21,从而维持PFK表达。他们的数据揭示了糖酵解对放线菌素细胞骨架的结构特征作出应答,从而将细胞代谢耦联到周围组织的机械特性的机制。这些过程使正常细胞能够在可变的微环境中调节能量产生,而尽管肿瘤组织的不断变化,细胞骨架应答机械信号形成的抗性仍使癌细胞具有高糖酵解速率。

据了解,细胞微环境的机制通过细胞骨架重塑和肌动球蛋白的收缩性不断调节细胞功能,例如生长、存活、凋亡、分化和形态发生。尽管所有这些过程都消耗能量,但细胞是否以及如何使它们的代谢活性适应可变的机械信号的,尚不清楚。

附:英文原文

Title: Mechanical regulation of glycolysis via cytoskeleton architecture

Author: Jin Suk Park, Christoph J. Burckhardt, Rossana Lazcano, Luisa M. Solis, Tadamoto Isogai, Linqing Li, Christopher S. Chen, Boning Gao, John D. Minna, Robert Bachoo, Ralph J. DeBerardinis, Gaudenz Danuser

Issue&Volume: 2020-02-12

Abstract: The mechanics of the cellular microenvironment continuously modulates cell functions such as growth, survival, apoptosis, differentiation and morphogenesis via cytoskeletal remodelling and actomyosin contractility1,2,3. Although all of these processes consume energy4,5, it is unknown whether and how cells adapt their metabolic activity to variable mechanical cues. Here we report that the transfer of human bronchial epithelial cells from stiff to soft substrates causes a downregulation of glycolysis via proteasomal degradation of the rate-limiting metabolic enzyme phosphofructokinase (PFK). PFK degradation is triggered by the disassembly of stress fibres, which releases the PFK-targeting E3 ubiquitin ligase tripartite motif (TRIM)-containing protein 21 (TRIM21). Transformed non-small-cell lung cancer cells, which maintain high glycolytic rates regardless of changing environmental mechanics, retain PFK expression by downregulating TRIM21, and by sequestering residual TRIM21 on a stress-fibre subset that is insensitive to substrate stiffness. Our data reveal a mechanism by which glycolysis responds to architectural features of the actomyosin cytoskeleton, thus coupling cell metabolism to the mechanical properties of the surrounding tissue. These processes enable normal cells to tune energy production in variable microenvironments, whereas the resistance of the cytoskeleton in response to mechanical cues enables the persistence of high glycolytic rates in cancer cells despite constant alterations of the tumour tissue.

DOI: 10.1038/s41586-020-1998-1

编辑:科学网:小柯机器人

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