The integrated stress response: From mechanism to disease.
The integrated stress response: From mechanism to disease.
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DOI：
10.1126/science.aat5314
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发表时间：
2020-04-24
期刊：
影响因子：
--
通讯作者：
Walter P
中科院分区：
文献类型：
--
作者：
Costa-Mattioli M;Walter P
综合应激反应（ISR）是一种进化上保守的细胞内信号网络，有助于细胞、组织和生物体适应变化的环境并保持健康。为了应对不同的环境和病理条件，包括蛋白质稳态缺陷、营养缺乏、病毒感染和氧化应激，ISR 通过重新编程基因表达来恢复平衡。四种特殊激酶（PERK、GCN2、PKR 和 HRI）可感知各种应激，这些激酶集中于真核翻译起始因子 eIF2 上单个丝氨酸的磷酸化。 eIF2 磷酸化会阻断 eIF2 的鸟嘌呤核苷酸交换因子（称为 eIF2B）的作用，导致蛋白质合成普遍减少。矛盾的是，eIF2 的磷酸化也会触发特定 mRNA 的翻译，包括关键转录因子，例如 ATF4。这些 mRNA 在其 5'-非翻译区中含有短的抑制性上游开放阅读框，可防止其典型 AUG 处的翻译起始。通过下调一般 mRNA 翻译并上调驱动新转录程序的一些蛋白质的合成，ISR 旨在维持或重建生理稳态。然而，如果应激无法缓解，ISR 就会触发细胞凋亡来消除受损细胞。我们对管理情监侦的核心机制的理解有了很大的进步。 ISR 的中央调控中心位于 eIF2-eIF2B 复合物，它控制 eIF2•GTP•甲硫氨酰启动子 tRNA 三元复合物 (TC) 的形成，这是启动新蛋白质合成的先决条件。功能性 TC 的组装受到 eIF2-P 的抑制，从而非竞争性地阻断 eIF2B。在哺乳动物细胞中，eIF2 的磷酸化是一个受到严格调控的过程。除了四种专门磷酸化 eIF2 的 eIF2 激酶外，还有两种专门的磷酸酶可以拮抗该反应。两种磷酸酶都包含一个共同的催化核心亚基，即蛋白磷酸酶 1 (PP1) 和一个调节亚基（GADD34 或 CReP），这使得磷酸酶对 eIF2 具有特异性。结构和生物物理方法已经阐明了 eIF2B 的作用机制及其通过 ISR 抑制剂和激活剂的调节。基因表达分析揭示了复杂的 ISR 驱动的重编程。尽管人们早就认识到，在大脑中，长期记忆的形成需要新的蛋白质合成，但最近不同物种和模型系统的因果证据和趋同证据表明，ISR 是这一过程的通用调节器。简而言之，抑制 ISR 会增强长期记忆的形成，而激活 ISR 则会阻止它。与这一观点相一致的是，无偏见的全基因组关联研究已经确定了智力障碍人类 ISR 关键组成部分的突变。此外，与年龄相关的认知障碍通常与 ISR 的激活有关。最值得注意的是，氧化应激、错误折叠的蛋白质和其他应激源会在包括阿尔茨海默氏病在内的多种神经退行性疾病中诱导 ISR。最近的遗传和药理学证据表明，调节 ISR 可以逆转认知功能障碍以及由蛋白质稳态缺陷引起的各种记忆障碍中的神经退行性变。因此，长期记忆缺陷可能主要是 ISR 激活的结果，而不是导致其诱导的特定蛋白质稳态缺陷。最后，ISR 还与许多其他复杂疾病的发病机制有关，包括癌症、糖尿病和代谢紊乱。 ISR 正在成为细胞和有机体水平上蛋白质稳态的中央调节器。从机制上讲，关于控制 TC 浓度的 eIF2B-eIF2 调节中心的额外输入，以及 ISR 与其他细胞内信号网络的连接，还有很多需要了解的地方。迄今为止，人们对在急性和持续 ISR 激活过程中合成发生改变的特定蛋白质的作用以及这些效应器如何协作计算细胞在 ISR 激活时做出的生或死决策知之甚少。 ISR 基因表达特征和功能后果需要在不同的组织、细胞类型和发育阶段进行绘制。此外，生成额外的遗传和分子工具将非常有价值，这些工具允许对特定细胞和电路中的 ISR 途径进行直接的时间和空间操作，以确定其功能。从医学角度来看，ISR 与多种疾病的病因有关，并且 ISR 的操纵正在成为治疗多种疾病的有前途的治疗途径。创新小鼠模型、患者来源的诱导多能干细胞和人类类器官的使用将大大增强我们进一步探索 ISR 临床相关性的能力，并帮助确定 ISR 调节可能有益的治疗窗口。鉴定 ISR 的其他特定小分子抑制剂和激活剂将为剖析 ISR 药理学在健康和疾病中的作用提供宝贵的机会。最后，对其他 ISR 调节剂的发现和机制理解将增加治疗靶点的范围，并可能进一步促进广泛的与年龄相关的人类疾病的临床开发。 ISR 的监管网络。稳态的各种偏差都会激活 ISR。由此产生的翻译失调会导致多种疾病。蛋白质质量控制对于细胞及其组成的生物体的正常功能至关重要。由此产生的蛋白质稳态（细胞蛋白质健康状况被监测并维持稳态的过程）的丧失与多种与年龄相关的人类疾病有关。在这里，我们重点介绍综合应激反应（ISR）（一种通过调节蛋白质合成速率来应对蛋白质稳态缺陷的中央信号网络）如何阻碍长期记忆的形成。此外，我们还探讨了 ISR 信号失调如何导致复杂疾病的发病机制，包括认知障碍、神经退行性疾病、癌症、糖尿病和代谢紊乱。调节 ISR 的工具的开发有望发现新的途径，以减少 ISR 引起的病理，从而获得临床益处。
The integrated stress response (ISR) is an evolutionarily conserved intracellular signaling network that helps the cell, tissue, and organism to adapt to a variable environment and maintain health. In response to different environmental and pathological conditions, including protein homeostasis (proteostasis) defects, nutrient deprivation, viral infection, and oxidative stress, the ISR restores balance by reprogramming gene expression. The various stresses are sensed by four specialized kinases (PERK, GCN2, PKR and HRI) that converge on phosphorylation of a single serine on the eukaryotic translation initiation factor eIF2. eIF2 phosphorylation blocks the action of eIF2’s guanine nucleotide exchange factor termed eIF2B, resulting in a general reduction in protein synthesis. Paradoxically, phosphorylation of eIF2 also triggers the translation of specific mRNAs, including key transcription factors, such as ATF4. These mRNAs contain short inhibitory upstream open reading frames in their 5′-untranslated regions that prevent translation initiation at their canonical AUGs. By tuning down general mRNA translation and up-regulating the synthesis of a few proteins that drive a new transcriptional program, the ISR aims to maintain or reestablish physiological homeostasis. However, if the stress cannot be mitigated, the ISR triggers apoptosis to eliminate the damaged cell. Our understanding of the central mechanisms that govern the ISR has advanced vastly. The ISR’s central regulatory hub lies in the eIF2-eIF2B complex, which controls the formation of the eIF2•GTP•methionyl-intiator tRNA ternary complex (TC), a prerequisite for initiating new protein synthesis. Assembly of functional TC is inhibited by eIF2-P, which blocks eIF2B noncompetitively. In mammalian cells, the phosphorylation of eIF2 is a tightly regulated process. In addition to the four specialized eIF2 kinases that phosphorylate eIF2, two dedicated phosphatases antagonize this reaction. Both phosphatases contain a common catalytic core subunit, the protein phosphatase 1 (PP1), and a regulatory subunit (GADD34 or CReP), which render the phosphatase specific to eIF2. Structural and biophysical approaches have elucidated the mechanism of action of eIF2B and its modulation by ISR inhibitors and activators. Gene expression analyses have revealed complex ISR-driven reprogramming. Although it has been long recognized that, in the brain, long-term memory formation requires new protein synthesis, recent causal and convergent evidence across different species and model systems has shown that the ISR serves as a universal regulator of this process. Briefly, inhibition of the ISR enhances long-term memory formation, whereas activation of the ISR prevents it. Consistent with this notion, unbiased genome-wide association studies have identified mutations in key components of the ISR in humans with intellectual disability. Furthermore, age-related cognitive disorders are commonly associated with the activation of the ISR. Most notably, oxidative stress, misfolded proteins, and other stressors induce the ISR in several neurodegenerative disorders, including Alzheimer’s disease. Recent genetic and pharmacological evidence suggest that tuning the ISR reverses cognitive dysfunction as well as neurodegeneration in a wide range of memory disorders that result from protein homeostasis defects. Thus, long-term memory deficits may primarily results as a consequence of ISR activation rather than from the particular proteostasis defects that lead to its induction. Finally, the ISR is also implicated in the pathogenesis of a plethora of other complex diseases, including cancer, diabetes, and metabolic disorders. The ISR is emerging as a central regulator of protein homeostasis at both the cellular and organismal level. Mechanistically, much remains to be understood regarding additional inputs into the eIF2B-eIF2 regulatory hub controlling TC concentration, as well as the ISR’s connectivity to other intracellular signaling networks. As yet, little is known about the role of the specific proteins whose synthesis is altered during acute and persistent ISR activation and how these effectors collaborate to compute the life or death decisions cells make upon ISR activation. ISR gene expression signatures and functional consequences will need to be mapped across different tissues, cell types, and developmental stages. In addition, it will be invaluable to generate additional genetic and molecular tools that permit the direct temporal and spatial manipulation of ISR pathway in specific cells and circuits to determine their function. From a medical perspective, the ISR is implicated in the etiology of several disorders, and manipulation of the ISR is emerging as a promising therapeutic avenue for the treatment of a variety of diseases. The use of innovative mouse models, patient-derived induced pluripotent stem cells, and human organoids will greatly enhance our ability to explore the ISR’s clinical relevance further and help define therapeutic windows in which ISR modulation may prove beneficial. Identifying additional specific small-molecule inhibitors and activators of the ISR will offer valuable opportunities to dissect the role of the ISR pharmacologically in health and disease. Finally, discovery and mechanistic understanding of additional ISR modulators will increase the repertoire of therapeutic targets and may further enable clinical development in a wide range of age-related human diseases. The regulatory network of the ISR. Diverse deviations from homeostasis activate the ISR. The resulting dysregulation of translation contributes to numerous diseases. Protein quality control is essential for the proper function of cells and the organisms that they make up. The resulting loss of proteostasis, the processes by which the health of the cell’s proteins is monitored and maintained at homeostasis, is associated with a wide range of age-related human diseases. Here, we highlight how the integrated stress response (ISR), a central signaling network that responds to proteostasis defects by tuning protein synthesis rates, impedes the formation of long-term memory. In addition, we address how dysregulated ISR signaling contributes to the pathogenesis of complex diseases, including cognitive disorders, neurodegeneration, cancer, diabetes, and metabolic disorders. The development of tools through which the ISR can be modulated promises to uncover new avenues to diminish pathologies resulting from it for clinical benefit.
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