Brostrom C O, Brostrom M A
Department of Pharmacology, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, Piscataway 08854, USA.
Prog Nucleic Acid Res Mol Biol. 1998;58:79-125. doi: 10.1016/s0079-6603(08)60034-3.
Chemicals and conditions that damage proteins, promote protein misfolding, or inhibit protein processing trigger the onset of protective homeostatic mechanisms resulting in "stress responses" in mammalian cells. Included in these responses are an acute inhibition of mRNA translation at the initiation step, a subsequent induction of various protein chaperones, and the recovery of mRNA translation. Separate, but closely related, stress response systems exist for the endoplasmic reticulum (ER), relating to the induction of specific "glucose-regulated proteins" (GRPs), and for the cytoplasm, pertaining to the induction of the "heat shock proteins" (HSPs). Activators of the ER stress response system, including Ca(2+)-mobilizing and thiol-reducing agents, are discussed and compared to activators of the cytoplasmic stress system, such as arsenite, heavy metal cations, and oxidants. An emerging integrative literature is reviewed that relates protein chaperones associated with cellular stress response systems to the coordinate regulation of translational initiation and protein processing. Background information is presented describing the roles of protein chaperones in the ER and cytoplasmic stress response systems and the relationships of chaperones and protein processing to the regulation of mRNA translation. The role of chaperones in regulating eIF-2 alpha kinase activities, eIF-2 cycling, and ribosomal loading on mRNA is emphasized. The putative role of GRP78 in coupling rates of translation to processing is modeled, and functional relationships between the HSP and GRP chaperone systems are discussed.
损害蛋白质、促使蛋白质错误折叠或抑制蛋白质加工的化学物质和条件会触发保护性稳态机制的启动，从而在哺乳动物细胞中引发“应激反应”。这些反应包括在起始步骤对mRNA翻译的急性抑制、随后各种蛋白质伴侣的诱导以及mRNA翻译的恢复。内质网（ER）存在独立但密切相关的应激反应系统，与特定“葡萄糖调节蛋白”（GRP）的诱导有关，而细胞质的应激反应系统则与“热休克蛋白”（HSP）的诱导有关。本文讨论了内质网应激反应系统的激活剂，包括钙离子动员剂和硫醇还原剂，并将其与细胞质应激系统的激活剂，如亚砷酸盐、重金属阳离子和氧化剂进行了比较。综述了一篇新兴的综合文献，该文献将与细胞应激反应系统相关的蛋白质伴侣与翻译起始和蛋白质加工过程中的协调调节联系起来。文中介绍了背景信息，描述了蛋白质伴侣在内质网和细胞质应激反应系统中的作用，以及伴侣蛋白和蛋白质加工与mRNA翻译调节的关系。重点强调了伴侣蛋白在调节eIF-2α激酶活性、eIF-2循环以及核糖体在mRNA上的加载中的作用。对GRP78在将翻译速率与加工过程耦合中的假定作用进行了建模，并讨论了HSP和GRP伴侣系统之间的功能关系。
