Stress-responsive regulation of extracellular proteostasis.
Stress-responsive regulation of extracellular proteostasis.
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DOI：
10.1083/jcb.202112104
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发表时间：
2022-04-04
期刊：
影响因子：
--
通讯作者：
Wiseman RL
中科院分区：
文献类型：
--
作者：
Mesgarzadeh JS;Buxbaum JN;Wiseman RL
Mesgarzadeh等人描述了调节细胞外蛋白质稳态网络的活性和组成的应激反应信号通路。遗传、环境和衰老相关的损伤可以促进与许多疾病的发病机制有关的分泌蛋白的错误折叠和随后的聚集。这引起了人们对理解负责调节细胞外环境如血液和脑脊液（CSF）中蛋白稳态的分子机制的极大兴趣。细胞外蛋白质稳态在很大程度上取决于生物学途径，包括伴侣蛋白、折叠酶和定位于ER和细胞外空间的降解因子。这些途径限制了细胞外环境中非天然的、潜在的易聚集蛋白质的积累。许多综述讨论了这些途径影响分泌蛋白质组构象完整性的分子机制。在这里，我们反而专注于描述的压力响应机制负责适应ER和细胞外蛋白质代谢途径，以保护分泌的蛋白质组从病理损伤，挑战这些环境。此外，我们强调新的策略，以确定参与调节细胞外蛋白质稳态的应激反应途径，并描述这些途径在人类疾病的病理和治疗意义。
Mesgarzadeh et al. describe the stress-responsive signaling pathways that regulate the activity and composition of the extracellular proteostasis network. Genetic, environmental, and aging-related insults can promote the misfolding and subsequent aggregation of secreted proteins implicated in the pathogenesis of numerous diseases. This has led to considerable interest in understanding the molecular mechanisms responsible for regulating proteostasis in extracellular environments such as the blood and cerebrospinal fluid (CSF). Extracellular proteostasis is largely dictated by biological pathways comprising chaperones, folding enzymes, and degradation factors localized to the ER and extracellular space. These pathways limit the accumulation of nonnative, potentially aggregation-prone proteins in extracellular environments. Many reviews discuss the molecular mechanisms by which these pathways impact the conformational integrity of the secreted proteome. Here, we instead focus on describing the stress-responsive mechanisms responsible for adapting ER and extracellular proteostasis pathways to protect the secreted proteome from pathologic insults that challenge these environments. Further, we highlight new strategies to identify stress-responsive pathways involved in regulating extracellular proteostasis and describe the pathologic and therapeutic implications for these pathways in human disease.
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