Laboratory of Fundamental Oncology, National Cancer Center Research Institute, Tsukiji 5-1-1, Chuo-ku, Tokyo, 104-0045, Japan.
Cellular Dynamics Laboratory, Cluster for Pioneering Research, RIKEN, 2-1 Hirosawa, Wako, Saitama, 351-0198, Japan.
Exp Cell Res. 2020 Jan 1;386(1):111686. doi: 10.1016/j.yexcr.2019.111686. Epub 2019 Nov 6.
IER5 gene encodes an activator of HSF1 and is a p53 target gene. The IER5 protein forms a ternary complex with HSF1 and PP2A, and promotes PP2A-dependent dephosphorylation of HSF1 at a number of serine and threonine residues. This hypo-phosphorylated form of HSF1 is transcriptionally active and has been suggested to be responsible for the HSF1 activation observed in cancers. Here we report that IER5 possess a classical bipartite nuclear localization signal (NLS) at amino acids 217-244 that is highly conserved among species and that mediates complex formation with importin-α and importin-β. We also demonstrate that the intact NLS is essential for HSF1 dephosphorylation and full activation by IER5. Thus, nuclear import of IER5 via importin-α and importin-β may be essential for IER5 function.
IER5 基因编码 HSF1 的激活物，是 p53 的靶基因。IER5 蛋白与 HSF1 和 PP2A 形成三元复合物，并促进 PP2A 依赖性地使 HSF1 的多个丝氨酸和苏氨酸残基去磷酸化。这种低磷酸化形式的 HSF1 具有转录活性，并被认为是导致癌症中观察到的 HSF1 激活的原因。在这里，我们报告 IER5 在氨基酸 217-244 处具有经典的双肽核定位信号（NLS），该信号在物种间高度保守，并与 importin-α 和 importin-β 形成复合物。我们还证明，完整的 NLS 对于 IER5 介导的 HSF1 去磷酸化和完全激活是必不可少的。因此，通过 importin-α 和 importin-β 的 IER5 核输入对于 IER5 的功能可能是必需的。
