Neuronal reprograming of protein homeostasis by calcium-dependent regulation of the heat shock response.
Neuronal reprograming of protein homeostasis by calcium-dependent regulation of the heat shock response.
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通过钙依赖性调节热休克反应对蛋白质稳态的神经元重编程。
DOI：
10.1371/journal.pgen.1003711
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发表时间：
2013-08
期刊：
影响因子：
4.5
通讯作者：
Morimoto RI
中科院分区：
文献类型：
--
作者：
Silva MC;Amaral MD;Morimoto RI
蛋白质质量控制需要持续监测以防止错误折叠、聚集和细胞功能丧失。越来越多的证据表明，在后生动物中，细胞之间的交流对于确保生物体健康和防止应激细胞和组织损害寿命具有重要作用。在这里，我们用C表示。elegans的研究表明，神经肌肉接头（NMJ）处生理胆碱能信号的适度增加诱导突触后肌肉细胞中HSF-1的钙（Ca 2+）依赖性激活，导致蛋白质错误折叠的抑制。这种对肌细胞蛋白质稳态的保护作用是在对蛋白质聚集修饰剂的无偏全基因组筛选中鉴定的，并且是由gei-11（Myb家族因子和L型乙酰胆碱受体（AChR）的拟议调节剂）的下调触发的。这反过来激活电压门控Ca 2+通道、EGL-19和肌浆网ryanodine受体以响应乙酰胆碱信号传导。钙释放到肌细胞的细胞质中激活Ca 2+依赖性激酶并诱导细胞质伴侣蛋白的HSF-1依赖性表达，其抑制亚稳态蛋白的错误折叠并稳定肌细胞的折叠环境。这表明热休克反应（HSR）可以在肌细胞中通过跨NMJ的神经元信号传导激活，以保护蛋白质组健康。蛋白质质量控制机制负责防止错误折叠和受损蛋白质的积累以及细胞功能的丧失。然而，细胞监视的能力是有限的，导致蛋白质聚集体的出现和年龄相关疾病的风险增加。在这里，我们表明，上调乙酰胆碱受体和适度增加胆碱能活性导致钙依赖性应激反应，抑制蛋白质错误折叠和恢复稳态C。elegans肌肉细胞这涉及乙酰胆碱受体的gei-11敲低依赖性上调，以及钙通过细胞膜和肌浆网特异性通道释放到肌细胞的细胞质中。随后，热休克因子1（HSF-1）的激活导致细胞质伴侣蛋白的表达，其抑制亚稳态和聚集蛋白的错误折叠，恢复折叠和肌肉功能。这揭示了一个新的非典型机制的细胞非自主调节的热休克反应，以确保细胞之间的平衡在后生动物。
Protein quality control requires constant surveillance to prevent misfolding, aggregation, and loss of cellular function. There is increasing evidence in metazoans that communication between cells has an important role to ensure organismal health and to prevent stressed cells and tissues from compromising lifespan. Here, we show in C. elegans that a moderate increase in physiological cholinergic signaling at the neuromuscular junction (NMJ) induces the calcium (Ca2+)-dependent activation of HSF-1 in post-synaptic muscle cells, resulting in suppression of protein misfolding. This protective effect on muscle cell protein homeostasis was identified in an unbiased genome-wide screening for modifiers of protein aggregation, and is triggered by downregulation of gei-11, a Myb-family factor and proposed regulator of the L-type acetylcholine receptor (AChR). This, in-turn, activates the voltage-gated Ca2+ channel, EGL-19, and the sarcoplasmic reticulum ryanodine receptor in response to acetylcholine signaling. The release of calcium into the cytoplasm of muscle cells activates Ca2+-dependent kinases and induces HSF-1-dependent expression of cytoplasmic chaperones, which suppress misfolding of metastable proteins and stabilize the folding environment of muscle cells. This demonstrates that the heat shock response (HSR) can be activated in muscle cells by neuronal signaling across the NMJ to protect proteome health. The protein quality control machinery is responsible for preventing the accumulation of misfolded and damaged proteins and loss of cellular function. The capacity of cellular surveillance is limited however, leading to increased appearance of protein aggregates and risk for age-associated diseases. Here, we show that upregulation of acetylcholine receptors and moderate increased cholinergic activity leads to a calcium-dependent stress response that suppresses protein misfolding and restores homeostasis in C. elegans muscle cells. This involves gei-11 knockdown-dependent upregulation of acetylcholine receptors, and the release of calcium into the cytoplasm of muscle cells through cell membrane and sarcoplasmic reticulum specific channels. Subsequently, activation of the heat shock factor 1 (HSF-1) leads to the expression of cytoplasmic chaperones that suppress misfolding of metastable and aggregating proteins, restoring folding and muscle function. This reveals a new non-canonical mechanism for the cell non-autonomous regulation of the heat shock response to ensure balance between cells in a metazoan.
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