Department of Anatomy and Neurobiology, University of Maryland School of Medicine, 20 Penn St, HSF2, S267, Baltimore, MD, 21201, USA.
Cell Stress Chaperones. 2020 Nov;25(6):929-941. doi: 10.1007/s12192-020-01128-7. Epub 2020 Jul 20.
The secretory pathway of neurons and endocrine cells contains a variety of mechanisms designed to combat cellular stress. These include not only the unfolded protein response pathways but also diverse chaperone proteins that collectively work to ensure proteostatic control of secreted and membrane-bound molecules. One of the least studied of these chaperones is the neural- and endocrine-specific molecule known as proSAAS. This small chaperone protein acts as a potent anti-aggregant both in vitro and in cellulo and also represents a cerebrospinal fluid biomarker in Alzheimer's disease. In the present study, we have examined the idea that proSAAS, like other secretory chaperones, might represent a stress-responsive protein. We find that exposure of neural and endocrine cells to the cell stressors tunicamycin and thapsigargin increases cellular proSAAS mRNA and protein in Neuro2A cells. Paradoxically, proSAAS secretion is inhibited by these same drugs. Exposure of Neuro2A cells to low concentrations of the hypoxic stress inducer cobalt chloride, or to sodium arsenite, an oxidative stressor, also increases cellular proSAAS content and reduces its secretion. We conclude that the cellular levels of the small secretory chaperone proSAAS are positively modulated by cell stress.
神经元和内分泌细胞的分泌途径包含多种旨在对抗细胞应激的机制。这些机制不仅包括未折叠蛋白反应途径，还包括各种伴侣蛋白，它们共同作用以确保分泌和膜结合分子的蛋白质稳态控制。在这些伴侣蛋白中，研究最少的是神经和内分泌特异性分子，即前蛋白原转化酶相关蛋白亚基（proSAAS）。这种小伴侣蛋白在体外和细胞内均具有很强的抗聚集作用，并且在阿尔茨海默病的脑脊液生物标志物中也有代表。在本研究中，我们研究了 proSAAS 是否像其他分泌伴侣蛋白一样可能代表应激反应蛋白的观点。我们发现，神经和内分泌细胞暴露于细胞应激原衣霉素和他普西汀会增加 Neuro2A 细胞中的细胞 proSAAS mRNA 和蛋白。矛盾的是，这些相同的药物会抑制 proSAAS 的分泌。Neuro2A 细胞暴露于低浓度的缺氧应激诱导剂氯化钴或氧化应激剂亚砷酸钠也会增加细胞内 proSAAS 的含量并减少其分泌。我们得出结论，细胞应激会正向调节小分泌伴侣蛋白 proSAAS 的细胞水平。
