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探讨大分子拥挤和 TNFR1 在细胞体积控制中的作用。

Exploring the role of macromolecular crowding and TNFR1 in cell volume control.

机构信息

School of Biological Sciences, Indian Association for the Cultivation of Science, Kolkata, India.

Department of Biological Sciences, Indian Institute of Science Education and Research Kolkata, Kolkata, India.

出版信息

Elife. 2024 Sep 19;13:e92719. doi: 10.7554/eLife.92719.

DOI:10.7554/eLife.92719
PMID:39297502
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11581439/
Abstract

The excessive cosolute densities in the intracellular fluid create a physicochemical condition called macromolecular crowding (MMC). Intracellular MMC entropically maintains the biochemical thermodynamic equilibria by favoring associative reactions while hindering transport processes. Rapid cell volume shrinkage during extracellular hypertonicity elevates the MMC and disrupts the equilibria, potentially ushering cell death. Consequently, cells actively counter the hypertonic stress through regulatory volume increase (RVI) and restore the MMC homeostasis. Here, we establish fluorescence anisotropy of EGFP as a reliable tool for studying cellular MMC and explore the spatiotemporal dynamics of MMC during cell volume instabilities under multiple conditions. Our studies reveal that the actin cytoskeleton enforces spatially varying MMC levels inside adhered cells. Within cell populations, MMC is uncorrelated with nuclear DNA content but anti-correlated with the cell spread area. Although different cell lines have statistically similar MMC distributions, their responses to extracellular hypertonicity vary. The intensity of the extracellular hypertonicity determines a cell's ability for RVI, which correlates with nuclear factor kappa beta (NFkB) activation. Pharmacological inhibition and knockdown experiments reveal that tumor necrosis factor receptor 1 (TNFR1) initiates the hypertonicity-induced NFkB signaling and RVI. At severe hypertonicities, the elevated MMC amplifies cytoplasmic microviscosity and hinders receptor interacting protein kinase 1 (RIPK1) recruitment at the TNFR1 complex, incapacitating the TNFR1-NFkB signaling and consequently, RVI. Together, our studies unveil the involvement of TNFR1-NFkB signaling in modulating RVI and demonstrate the pivotal role of MMC in determining cellular osmoadaptability.

摘要

细胞内液中过多的共溶质密度会产生一种称为大分子拥挤（MMC）的物理化学条件。细胞内 MMC 通过有利于缔合反应而阻碍运输过程，在熵方面维持着生物化学热力学平衡。细胞外高渗时细胞快速体积收缩会增加 MMC 并破坏平衡，可能导致细胞死亡。因此，细胞通过调节体积增加（RVI）积极应对高渗应激，并恢复 MMC 平衡。在这里，我们建立了 EGFP 的荧光各向异性作为研究细胞 MMC 的可靠工具，并在多种条件下研究细胞体积不稳定期间 MMC 的时空动力学。我们的研究表明，肌动蛋白细胞骨架在贴壁细胞内强制执行空间变化的 MMC 水平。在细胞群体中，MMC 与核 DNA 含量无关，但与细胞扩展面积呈反相关。尽管不同的细胞系具有统计学上相似的 MMC 分布，但它们对外界高渗的反应不同。细胞对外界高渗的耐受能力与核因子 kappa beta（NFkB）的激活相关，取决于细胞外高渗的强度。药理学抑制和敲低实验表明，肿瘤坏死因子受体 1（TNFR1）启动高渗诱导的 NFkB 信号和 RVI。在严重的高渗条件下，升高的 MMC 会放大细胞质微粘度，并阻碍受体相互作用蛋白激酶 1（RIPK1）在 TNFR1 复合物上的募集，使 TNFR1-NFkB 信号和 RVI 失效。总之，我们的研究揭示了 TNFR1-NFkB 信号在调节 RVI 中的作用，并证明了 MMC 在确定细胞渗透适应性中的关键作用。

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