Institute of Neuropathology, RWTH Aachen University Hospital, Pauwelsstr. 30, 52074, Aachen, Germany.
Leibniz-Institut für Analytische Wissenschaften - ISAS - e.V, Otto-Hahn-Str. 6b, 44227, Dortmund, Germany.
Mol Neurobiol. 2018 Mar;55(3):2524-2546. doi: 10.1007/s12035-017-0494-6. Epub 2017 Apr 11.
SIL1 acts as a co-chaperone for the major ER-resident chaperone BiP and thus plays a role in many BiP-dependent cellular functions such as protein-folding control and unfolded protein response. Whereas the increase of BiP upon cellular stress conditions is a well-known phenomenon, elevation of SIL1 under stress conditions was thus far solely studied in yeast, and different studies indicated an adverse effect of SIL1 increase. This is seemingly in contrast with the beneficial effect of SIL1 increase in surviving neurons in neurodegenerative disorders such as amyotrophic lateral sclerosis and Alzheimer's disease. Here, we addressed these controversial findings. Applying cell biological, morphological and biochemical methods, we demonstrated that SIL1 increases in various mammalian cells and neuronal tissues upon cellular stress. Investigation of heterozygous SIL1 mutant cells and tissues supported this finding. Moreover, SIL1 protein was found to be stabilized during ER stress. Increased SIL1 initiates ER stress in a concentration-dependent manner which agrees with the described adverse SIL1 effect. However, our results also suggest that protective levels are achieved by the secretion of excessive SIL1 and GRP170 and that moderately increased SIL1 also ameliorates cellular fitness under stress conditions. Our immunoprecipitation results indicate that SIL1 might act in a BiP-independent manner. Proteomic studies showed that SIL1 elevation alters the expression of proteins including crucial players in neurodegeneration, especially in Alzheimer's disease. This finding agrees with our observation of increased SIL1 immunoreactivity in surviving neurons of Alzheimer's disease autopsy cases and supports the assumption that SIL1 plays a protective role in neurodegenerative disorders.
SIL1 作为主要内质网驻留伴侣蛋白 BiP 的共伴侣，因此在许多依赖 BiP 的细胞功能中发挥作用，如蛋白质折叠控制和未折叠蛋白反应。虽然细胞应激条件下 BiP 的增加是一种众所周知的现象，但应激条件下 SIL1 的升高迄今为止仅在酵母中进行了研究，并且不同的研究表明 SIL1 增加的不良影响。这似乎与 SIL1 在肌萎缩侧索硬化症和阿尔茨海默病等神经退行性疾病中存活神经元中增加的有益效果相矛盾。在这里，我们解决了这些有争议的发现。应用细胞生物学、形态学和生化方法，我们证明了各种哺乳动物细胞和神经元组织在细胞应激时 SIL1 增加。对杂合 SIL1 突变细胞和组织的研究支持了这一发现。此外，发现 SIL1 蛋白在 ER 应激期间稳定。增加的 SIL1 以浓度依赖的方式引发 ER 应激，这与描述的不良 SIL1 效应一致。然而，我们的结果还表明，通过过度分泌 SIL1 和 GRP170 达到保护水平，并且适度增加的 SIL1 也可以改善应激条件下的细胞适应性。我们的免疫沉淀结果表明 SIL1 可能以 BiP 独立的方式发挥作用。蛋白质组学研究表明，SIL1 升高改变了蛋白质的表达，包括神经退行性变中的关键参与者，特别是在阿尔茨海默病中。这一发现与我们在阿尔茨海默病尸检病例中存活神经元中 SIL1 免疫反应性增加的观察结果一致，并支持 SIL1 在神经退行性疾病中发挥保护作用的假设。
