A novel function of the monomeric CCTε subunit connects the serum response factor pathway to chaperone-mediated actin folding.
A novel function of the monomeric CCTε subunit connects the serum response factor pathway to chaperone-mediated actin folding.
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DOI：
10.1091/mbc.e15-01-0048
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发表时间：
2015-08-01
影响因子：
3.3
通讯作者：
Grantham J
中科院分区：
文献类型：
--
作者：
Elliott KL;Svanström A;Spiess M;Karlsson R;Grantham J
CCTε 是寡聚 CCT 分子伴侣的一个亚基，与共转录因子 MRTF-A 相互作用，从而影响血清刺激后 MRTF-A 的核积累。这确立了 CCTε 在单体时的新功能，并揭示了 CCT 在肌动蛋白严格质量控制中的扩展作用。正确的蛋白质折叠对于维持蛋白质稳态和避免形成潜在的细胞毒性蛋白质聚集体至关重要。尽管有些蛋白质似乎无需辅助即可折叠，但肌动蛋白需要寡聚分子伴侣 CCT 的帮助。在这里，我们通过鉴定 CCT 亚基之一 CCTε 作为心肌素相关共转录因子 A (MRTF-A)/血清反应因子 (SRF) 途径的组成部分，报告了 CCT 和肌动蛋白之间的额外联系。 SRF 通路记录 G-肌动蛋白水平的变化，导致肌动蛋白聚合后大量基因的转录上调。这些基因编码许多肌动蛋白结合蛋白以及肌动蛋白。我们发现，通过 siRNA 消除 CCTε 亚基，可以通过肌动蛋白组装独立机制增强培养的哺乳动物细胞中的 SRF 信号传导。单体形式的 CCTε 过表达表明，CCTε 通过其底物结合结构域与 MRTF-A 的 C 末端区域结合，并且 CCTε 在添加血清刺激后能够改变 MRTF-A 的核积累。鉴于单体 CCTε 的水平反过来反映了 CCT 寡聚体的水平，我们的结果表明 CCTε 提供了细胞肌动蛋白折叠能力和肌动蛋白表达之间的联系。
CCTε, a subunit of the oligomeric CCT molecular chaperone, interacts with the cotranscription factor MRTF-A, thus influencing MRTF-A nuclear accumulation upon serum stimulation. This establishes a novel function for CCTε when monomeric and reveals an extended role for CCT in the stringent quality control of actin. Correct protein folding is fundamental for maintaining protein homeostasis and avoiding the formation of potentially cytotoxic protein aggregates. Although some proteins appear to fold unaided, actin requires assistance from the oligomeric molecular chaperone CCT. Here we report an additional connection between CCT and actin by identifying one of the CCT subunits, CCTε, as a component of the myocardin-related cotranscription factor-A (MRTF-A)/serum response factor (SRF) pathway. The SRF pathway registers changes in G-actin levels, leading to the transcriptional up-regulation of a large number of genes after actin polymerization. These genes encode numerous actin-binding proteins as well as actin. We show that depletion of the CCTε subunit by siRNA enhances SRF signaling in cultured mammalian cells by an actin assembly-independent mechanism. Overexpression of CCTε in its monomeric form revealed that CCTε binds via its substrate-binding domain to the C-terminal region of MRTF-A and that CCTε is able to alter the nuclear accumulation of MRTF-A after stimulation by serum addition. Given that the levels of monomeric CCTε conversely reflect the levels of CCT oligomer, our results suggest that CCTε provides a connection between the actin-folding capacity of the cell and actin expression.