Department of Biology, Center for Cellular Dynamics, Pennsylvania State University, University Park, Pennsylvania, United States of America.
PLoS One. 2011;6(8):e23740. doi: 10.1371/journal.pone.0023740. Epub 2011 Aug 18.
The ER chaperone GRP78/BiP is a homolog of the Hsp70 family of heat shock proteins, yet GRP78/BiP is not induced by heat shock but instead by ER stress. However, previous studies had not considered more physiologically relevant temperature elevation associated with febrile hyperthermia. In this report we examine the response of GRP78/BiP and other components of the ER stress pathway in cells exposed to 40°C.
AD293 cells were exposed to 43°C heat shock to confirm inhibition of the ER stress response genes. Five mammalian cell types, including AD293 cells, were then exposed to 40°C hyperthermia for various time periods and induction of the ER stress pathway was assessed.
The inhibition of the ER stress pathway by heat shock (43°C) was confirmed. In contrast cells subjected to more mild temperature elevation (40°C) showed either a partial or full ER stress pathway induction as determined by downstream targets of the three arms of the ER stress pathway as well as a heat shock response. Cells deficient for Perk or Gcn2 exhibit great sensitivity to ER stress induction by hyperthermia.
The ER stress pathway is induced partially or fully as a consequence of hyperthermia in parallel with induction of Hsp70. These findings suggest that the ER and cytoplasm of cells contain parallel pathways to coordinately regulate adaptation to febrile hyperthermia associated with disease or infection.
内质网伴侣 GRP78/BiP 是热休克蛋白 Hsp70 家族的同源物，但 GRP78/BiP 不是由热休克诱导的，而是由内质网应激诱导的。然而，以前的研究并没有考虑与发热性高热相关的更具生理相关性的温度升高。在本报告中，我们研究了暴露于 40°C 下的细胞中 GRP78/BiP 和内质网应激途径的其他成分的反应。
将 AD293 细胞暴露于 43°C 的热休克以确认对 ER 应激反应基因的抑制。然后，将五种哺乳动物细胞类型（包括 AD293 细胞）暴露于 40°C 的过热，持续不同的时间，并评估 ER 应激途径的诱导。
通过热休克（43°C）抑制 ER 应激途径得到了证实。相比之下，暴露于更温和的温度升高（40°C）的细胞显示出 ER 应激途径的部分或完全诱导，如 ER 应激途径的三个分支的下游靶标以及热休克反应所示。缺乏 Perk 或 Gcn2 的细胞对过热诱导的 ER 应激非常敏感。
与热休克诱导的 HSP70 平行，内质网应激途径部分或完全被诱导。这些发现表明，细胞的内质网和细胞质包含平行途径，以协调调节与疾病或感染相关的发热性高热适应。
