ER stress causes widespread protein aggregation and prion formation.
ER stress causes widespread protein aggregation and prion formation.
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DOI：
10.1083/jcb.201612165
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发表时间：
2017-08-07
期刊：
影响因子：
--
通讯作者：
Grant CM
中科院分区：
文献类型：
--
作者：
Hamdan N;Kritsiligkou P;Grant CM
ER应激导致不定位于ER或分泌系统的一部分的蛋白质的广泛聚集。Hamdan等人证明，无定形和淀粉样蛋白聚集是扰乱ER稳态的间接结果。内质网（ER）稳态的紊乱产生了一种称为ER应激的状况。这激活了未折叠蛋白反应（UPR），这改变了许多参与ER质量控制的基因的表达。我们在这里表明，ER应激导致蛋白质的聚集，其中大部分不是ER或分泌途径蛋白质。聚集的蛋白质的蛋白质组学分析揭示了富集的内在的聚集倾向的蛋白质，而不是蛋白质的压力特定的方式受到影响。聚集并不是因为蛋白酶体介导的降解，而是因为细胞蛋白质稳态的普遍破坏。我们进一步表明，某些分子伴侣的过度表达废除蛋白质聚集和保护UPR突变体对ER应激条件。ER应激的发生与各种疾病过程相关，我们的数据表明，广泛的无定形和淀粉样蛋白聚集是这种应激的意外结果。
ER stress results in widespread aggregation of proteins that are not localized to the ER or are part of the secretory system. Hamdan et al. demonstrate that amorphous and amyloidogenic protein aggregation is an indirect consequence of perturbing ER homeostasis. Disturbances in endoplasmic reticulum (ER) homeostasis create a condition termed ER stress. This activates the unfolded protein response (UPR), which alters the expression of many genes involved in ER quality control. We show here that ER stress causes the aggregation of proteins, most of which are not ER or secretory pathway proteins. Proteomic analysis of the aggregated proteins revealed enrichment for intrinsically aggregation-prone proteins rather than proteins which are affected in a stress-specific manner. Aggregation does not arise because of overwhelming proteasome-mediated degradation but because of a general disruption of cellular protein homeostasis. We further show that overexpression of certain chaperones abrogates protein aggregation and protects a UPR mutant against ER stress conditions. The onset of ER stress is known to correlate with various disease processes, and our data indicate that widespread amorphous and amyloid protein aggregation is an unanticipated outcome of such stress.
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