Salt, skeletons, and suicide. Focus on "Hyperosmotic stress regulates the distribution and stability of myocardin-related transcription factor, a key modulator of the cytoskeleton".
Salt, skeletons, and suicide. Focus on "Hyperosmotic stress regulates the distribution and stability of myocardin-related transcription factor, a key modulator of the cytoskeleton".
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盐、骷髅和自杀。
DOI：
10.1152/ajpcell.00319.2012
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发表时间：
2013
期刊：
影响因子：
--
通讯作者：
Ferraris,JoanD
中科院分区：
文献类型：
--
作者：
Burg,MauriceB;Ferraris,JoanD
高氯化钠和其他高渗来源是跨越进化的细胞压力。大多数生物体常见的保护性反应是相容性有机渗透剂的细胞积累，这是由转运蛋白和合成酶的转录增加驱动的。在哺乳动物细胞中，转录因子 NFAT5 (TonEBP/OREBP) 驱动高渗诱导的转运蛋白转录和合成酶，从而增加保护性有机渗透剂 (1)。 NFAT5 仍然是唯一已知的渗透保护哺乳动物转录因子。然而，现在，Ly 等人(5) 新发现了血清反应因子 (SRF) 作为一种额外的渗透保护转录因子，其高 NaCl 的激活依赖于辅助调节因子 MRTF [巨核细胞白血病（易位）1，MKL1]。对于我们这些对细胞对渗透压的反应感兴趣的人来说，这是一个令人兴奋的消息。高渗性会导致细胞骨架快速重排 (3)。 Ly 等人 (5) 表明，在肾上皮细胞 (LLC-PK1) 中，这会导致 MRTF 快速核转位（图 1），尽管它的名称是（心肌素相关转录因子），但在这种情况下，它充当 SRF 的共调节因子。 MRTF 基因有两个，即 MRTF-A (MLK1) 和 MRTF-B (MLK2)。 Ly 等人(5) 在不区分异构体时参考 MRTF。在正常张力条件下，MRTF 通过与球状肌动蛋白 (G-肌动蛋白) 结合而被限制在细胞质中。 MRTF 拥有独特的 NH2 末端 RPEL 结构域，可介导其与 G 肌动蛋白的相互作用。 G-肌动蛋白与 MRTF 结合可阻止输入蛋白 α/β 进入 MRTF 核定位序列 (NLS)，从而阻止核输入。高渗性会激活 Rho 鸟嘌呤核苷酸交换因子 GEF-H1，进而激活 RhoA/Rho 激酶 (ROK) 途径，导致 G 肌动蛋白聚合为 F 肌动蛋白并释放结合的 MRTF。释放 MRTF 会暴露其核定位信号，从而促进其核积累。核 MRTF 共激活 SRF，SRF 是一种与位于 SRF 靶基因调控区域的血清反应元件 [SRE 或 CC (AT) 6GG 顺式元件，也称为 CArG 盒] 结合的转录因子。 SRF是一种双功能转录因子，可反式激活两类不同的基因，即增殖/存活促进早期基因和细胞骨架/肌肉分化特异性基因。 SRF 激活哪组基因取决于核心调节因子。 ETS结构域蛋白的三元复合因子家族将SRF活性引导至对血清的早期基因反应（例如c-fos）； MRTF 将 SRF 活性引导至细胞骨架/肌肉分化特异性基因 (6, 7)。除了增加细胞核 MRTF 之外，高渗状态还会激活 p38 MAPK，有趣的是，它会减轻细胞核中 MRTF 的增加 (5)。 p38 缓解的证据是，用 SB203580（一种有效的 p38 抑制剂）预处理细胞，在等渗条件下对 MRTF 分布没有显着影响，但在存在抑制剂的情况下，渗透压会诱导明显更强的核 MRTF 积累。但请记住，SB203580 的影响可能难以解释。高渗会激活 p38 的两种同工型（p38α 和 p38δ），这些同工型在高渗情况下具有相反的作用 (8)。 p38α 增强高渗诱导的 NFAT5 激活，而 p38δ 则抑制它。 SB203580 抑制 p38α，但不抑制 p38δ，并且用于估计 p38 活性的磷酸特异性抗体不能区分 p38α 和 p38δ。虽然 p38α 增强高渗诱导的 NFAT5 激活，但它不会影响高渗诱导的核定位……
HIGH NaCl AND OTHER SOURCES of hypertonicity are cellular stresses that span evolution. A protective response common to most organisms is cellular accumulation of compatible organic osmolytes, driven by increased transcription of transporters and synthesizing enzymes. In mammalian cells the transcription factor NFAT5 (TonEBP/OREBP) drives the hypertonicityinduced transcription of transporters and synthesizing enzymes that increase protective organic osmolytes (1). NFAT5 has remained the only known osmoprotective mammalian transcription factor. Now, however, Ly et al.(5) have newly identified serum response factor (SRF) as an additional osmoprotective transcription factor whose activation by high NaCl depends on a coregulator, MRTF [megakaryoblastic leukemia (translocation) 1, MKL1]. This is exciting news for those of us interested in cellular responses to osmotic stress. Hypertonicity induces rapid cytoskeletal rearrangement (3). Ly et al.(5) show that, in kidney epithelial cells (LLC-PK1), this causes rapid nuclear translocation of MRTF (Fig. 1), which despite its name (myocardin-related transcription factor), acts in this instance as a coregulator of SRF. There are two MRTF genes, namely MRTF-A (MLK1) and MRTF-B (MLK2). Ly et al.(5) refer to MRTF when not distinguishing between the isoforms. Under normotonic conditions, MRTF is restricted to the cytoplasm by binding to globular actin (G-actin). MRTF possesses a unique NH2-terminal RPEL domain which mediates its interaction with G-actin. G-actin binding to MRTF prevents importin α/β access to the MRTF nuclear localization sequence (NLS) and, thus, blocks nuclear import. Hypertonicity activates the Rho guanine nucleotide exchange factor, GEF-H1, which, in turn, activates the RhoA/Rho kinase (ROK) pathway, resulting in polymerization of G-actin to F-actin and liberation of the bound MRTF. Freeing MRTF unmasks its nuclear localization signal, thereby promoting its nuclear accumulation. Nuclear MRTF coactivates SRF, a transcription factor that binds to serum response elements [SREs or CC (AT) 6GG cis-elements, also called CArG boxes] located in regulatory regions of SRF target genes. SRF is a dual-function transcription factor that transactivates two different classes of genes, namely proliferation/survival-promoting early genes and cytoskeleton/muscle differentiation-specific genes. Which set of genes is activated by SRF depends on coregulators. The ternary complex factor family of ETS domain proteins directs SRF activity to the immediate early gene response to serum (eg, c-fos); MRTF directs SRF activity to cytoskeleton/muscle differentiation-specific genes (6, 7). In addition to increasing nuclear MRTF, hypertonicity also activates p38 MAPK, which interestingly mitigates the increase of MRTF in the nucleus (5). The evidence for mitigation by p38 is that pretreatment of cells with SB203580, a potent p38 inhibitor, had no significant effect on MRTF distribution under isotonic conditions, but osmotic stress induced markedly stronger nuclear MRTF accumulation in the presence of the inhibitor. Keep in mind, however, that the effects of SB203580 can be difficult to interpret. Hypertonicity activates two of the isoforms of p38 (p38α and p38δ), and these isoforms have opposite effects in the context of hypertonicity (8). p38α enhances hypertonicity-induced activation of NFAT5, while p38δ inhibits it. SB203580 inhibits p38α, but not p38δ, and the phosphospecific antibodies used to estimate p38 activity do not distinguish between p38α and p38δ. Although p38α enhances hypertonicity-induced activation of NFAT5, it does not affect hypertonicity-induced nuclear localization of …