Hamdan Norfadilah, Kritsiligkou Paraskevi, Grant Chris M
Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, England, UK.
Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, England, UK
J Cell Biol. 2017 Aug 7;216(8):2295-2304. doi: 10.1083/jcb.201612165. Epub 2017 Jun 19.
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.
内质网（ER）稳态的紊乱会产生一种称为内质网应激的状态。这会激活未折叠蛋白反应（UPR），从而改变许多参与内质网质量控制的基因的表达。我们在此表明，内质网应激会导致蛋白质聚集，其中大多数并非内质网或分泌途径蛋白。对聚集蛋白的蛋白质组学分析显示，富含内在易聚集蛋白，而非以应激特异性方式受到影响的蛋白。聚集并非由于蛋白酶体介导的降解不堪重负所致，而是由于细胞蛋白质稳态的普遍破坏。我们进一步表明，某些伴侣蛋白的过表达可消除蛋白质聚集，并保护UPR突变体免受内质网应激条件的影响。已知内质网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。
