Maintenance of the proteome, ensuring the proper locations, proper conformations, appropriate concentrations, etc., is essential to preserve the health of an organism in the face of environmental insults, infectious diseases, and the challenges associated with aging. Maintaining the proteome is even more difficult in the background of inherited mutations that render a given protein and others handled by the same proteostasis machinery misfolding prone and/or aggregation prone. Maintenance of the proteome or maintaining proteostasis requires the orchestration of protein synthesis, folding, trafficking, and degradation by way of highly conserved, interacting, and competitive proteostasis pathways. Each subcellular compartment has a unique proteostasis network compromising common and specialized proteostasis maintenance pathways. Stress-responsive signaling pathways detect the misfolding and/or aggregation of proteins in specific subcellular compartments using stress sensors and respond by generating an active transcription factor. Subsequent transcriptional programs up-regulate proteostasis network capacity (i.e., ability to fold and degrade proteins in that compartment). Stress-responsive signaling pathways can also be linked by way of signaling cascades to nontranscriptional means to reestablish proteostasis (e.g., by translational attenuation). Proteostasis is also strongly influenced by the inherent kinetics and thermodynamics of the folding, misfolding, and aggregation of individual proteins, and these sequence-based attributes in combination with proteostasis network capacity together influence proteostasis. In this review, we will focus on the growing body of evidence that proteostasis deficits leading to human pathology can be reversed by pharmacologic adaptation of proteostasis network capacity through stress-responsive signaling pathway activation. The power of this approach will be exemplified by focusing on the ATF6 arm of the unfolded protein response stress responsive-signaling pathway that regulates proteostasis network capacity of the secretory pathway.

中文翻译：

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适应分泌途径中的蛋白质稳态以改善蛋白质构象疾病的药理学方法。


蛋白质组的维护，确保适当的位置、适当的构象、适当的浓度等，对于在面对环境侵害、传染病和与衰老相关的挑战时保持生物体的健康至关重要。在遗传突变的背景下，维持蛋白质组变得更加困难，遗传突变使得给定蛋白质和由相同蛋白质稳态机制处理的其他蛋白质容易错误折叠和/或容易聚集。蛋白质组的维持或维持蛋白质稳态需要通过高度保守、相互作用和竞争性的蛋白质稳态途径来协调蛋白质合成、折叠、运输和降解。每个亚细胞区室都有一个独特的蛋白质稳态网络，损害常见和专门的蛋白质稳态维持途径。应激反应信号通路使用应激传感器检测特定亚细胞区室中蛋白质的错误折叠和/或聚集，并通过生成活性转录因子进行响应。随后的转录程序上调蛋白质稳态网络能力（即，在该区室中折叠和降解蛋白质的能力）。应激反应信号传导途径也可以通过信号级联与非转录手段连接以重建蛋白质稳态（例如，通过翻译减弱）。蛋白质稳态还受到单个蛋白质的折叠、错误折叠和聚集的固有动力学和热力学的强烈影响，并且这些基于序列的属性与蛋白质稳态网络能力相结合共同影响蛋白质稳态。 在这篇综述中，我们将重点关注越来越多的证据，表明导致人类病理的蛋白质稳态缺陷可以通过应激反应信号通路激活对蛋白质稳态网络能力的药理适应来逆转。这种方法的力量将通过关注未折叠蛋白反应应激反应信号通路的 ATF6 臂来举例说明，该通路调节分泌通路的蛋白稳态网络能力。