Endoplasmic reticulum quality control and systemic amyloid disease: Impacting protein stability from the inside out.
Endoplasmic reticulum quality control and systemic amyloid disease: Impacting protein stability from the inside out.
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DOI：
10.1002/iub.1386
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发表时间：
2015-06
期刊：
影响因子：
4.6
通讯作者：
Wiseman, R. Luke
中科院分区：
文献类型：
--
作者：
Chen, John J.;Genereux, Joseph C.;Wiseman, R. Luke
内质网（ER）在整个分泌途径中负责调节蛋白质组的完整性。内质网通过在内质网蛋白折叠、转运和降解途径之间分配蛋白质来保护下游的分泌环境，如细胞外空间，这一过程被称为内质网质量控制。在这一过程中，内质网质量控制因子识别出错误折叠、容易聚集的蛋白质构象，并将其导向内质网蛋白折叠或降解，减少内质网蛋白分泌到细胞外空间，从而进一步错误折叠或聚集成蛋白质毒性构象。尽管内质网质量控制一般有效，但许多人类疾病，如系统性淀粉样变性，涉及不稳定的、易聚集的蛋白质在细胞外空间聚集。所有系统性淀粉样蛋白疾病的一个共同特征是淀粉样蛋白能够逃避内质网质量控制并有效分泌。这些淀粉样蛋白的有效分泌增加了其血清浓度，可用于这些疾病的远端蛋白毒性聚集特征。这表明内质网质量控制及其调控是确定全身性淀粉样蛋白疾病发病和病理的关键决定因素。在此，我们讨论内质网质量控制、蛋白分泌和淀粉样蛋白远端沉积与全身性淀粉样蛋白疾病之间的病理和潜在治疗关系。此外，我们提供的证据表明，未折叠蛋白反应，即调节内质网质量控制的应激反应信号通路，参与了全身性淀粉样蛋白疾病的发病机制，并代表了干预这类人类疾病的一个有希望的新兴治疗靶点。
The endoplasmic reticulum (ER) is responsible for regulating proteome integrity throughout the secretory pathway. The ER protects downstream secretory environments such as the extracellular space by partitioning proteins between ER protein folding, trafficking and degradation pathways in a process called ER quality control. In this process, ER quality control factors identify misfolded, aggregation-prone protein conformations and direct them towards ER protein folding or degradation, reducing their secretion to the extracellular space where they could further misfold or aggregate into proteotoxic conformations. Despite the general efficiency of ER quality control, many human diseases, such as the systemic amyloidoses, involve aggregation of destabilized, aggregation-prone proteins in the extracellular space. A common feature for all systemic amyloid diseases is the ability for amyloidogenic proteins to evade ER quality control and be efficiently secreted. The efficient secretion of these amyloidogenic proteins increases their serum concentrations available for the distal proteotoxic aggregation characteristic of these diseases. This indicates that ER quality control, and the regulation thereof, is a critical determinant in defining the onset and pathology of systemic amyloid diseases. Here, we discuss the pathologic and potential therapeutic relationship between ER quality control, protein secretion and distal deposition of amyloidogenic proteins involved in systemic amyloid diseases. Furthermore, we present evidence that the Unfolded Protein Response, the stress-responsive signaling pathway that regulates ER quality control, is involved in the pathogenesis of systemic amyloid diseases and represents a promising emerging therapeutic target to intervene in this class of human disease.
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影响因子：
33.6
作者：
Guerriero CJ;Brodsky JL
通讯作者：
Brodsky JL
影响因子：
8.8
作者：
Gillmore, J. D.;Stangou, A. J.;Hawkins, P. N.
通讯作者：
Hawkins, P. N.
DOI：
10.1073/pnas.1121005109
发表时间：
2012-06-12
影响因子：
11.1
作者：
Bulawa, Christine E.;Connelly, Stephen;Labaudiniere, Richard
通讯作者：
Labaudiniere, Richard
影响因子：
4.4
作者：
Chiang, Wei-Chieh;Hiramatsu, Nobuhiko;Lin, Jonathan H.
通讯作者：
Lin, Jonathan H.
影响因子：
168.9
作者：
HOLMGREN, G;ERICZON, BG;PEPYS, MB
通讯作者：
PEPYS, MB