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缺乏 Hikeshi 在正常情况下会激活 HSF1 的活性，并扰乱热休克反应。

Lack of Hikeshi activates HSF1 activity under normal conditions and disturbs the heat-shock response.

机构信息

Cellular Dynamics Laboratory, RIKEN Cluster for Pioneering Research, Wako, Japan

Cellular and Molecular Biotechnology Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Tokyo, Japan.

出版信息

Life Sci Alliance. 2022 May 17;5(9). doi: 10.26508/lsa.202101241. Print 2022 Sep.

DOI:10.26508/lsa.202101241
PMID:35580988
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9113944/
Abstract

Hikeshi mediates the nuclear import of the molecular chaperone HSP70 under heat-shock (acute heat stress) conditions, which is crucial for recovery from cellular damage. The cytoplasmic function of HSP70 is well studied, but its nuclear roles, particularly under nonstressed conditions, remain obscure. Here, we show that Hikeshi regulates the nucleocytoplasmic distribution of HSP70 not only under heat-shock conditions but also under nonstressed conditions. Nuclear HSP70 affects the transcriptional activity of HSF1 and nuclear proteostasis under nonstressed conditions. Depletion of Hikeshi induces a reduction in nuclear HSP70 and up-regulation of the mRNA expression of genes regulated by HSF1 under nonstressed conditions. In addition, the heat-shock response is impaired in Hikeshi-knockout cells. Our results suggest that HSF1 transcriptional activity is tightly regulated by nuclear HSP70 because nuclear-localized Hsp70 effectively suppresses transcriptional activity in a dose-dependent manner. Furthermore, the cytotoxicity of nuclear pathologic polyglutamine proteins was increased by Hikeshi depletion. Thus, proper nucleocytoplasmic distribution of HSP70, mediated by Hikeshi, is required for nuclear proteostasis and adaptive response to heat shock.

摘要

hikeshi 介导 HSP70 分子伴侣在热休克（急性热应激）条件下的核输入，这对于从细胞损伤中恢复至关重要。HSP70 的细胞质功能研究得很好，但它的核功能，特别是在非应激条件下，仍然不清楚。在这里，我们表明 hikeshi 不仅在热休克条件下，而且在非应激条件下调节 HSP70 的核质分布。核 HSP70 影响 HSF1 的转录活性和非应激条件下的核蛋白稳态。Hikeshi 的耗竭诱导核 HSP70 的减少和非应激条件下受 HSF1 调节的基因的 mRNA 表达上调。此外，Hikeshi 敲除细胞的热休克反应受损。我们的结果表明，HSF1 的转录活性受到核 HSP70 的严格调控，因为核定位的 Hsp70 以剂量依赖的方式有效地抑制转录活性。此外，核病理性多聚谷氨酰胺蛋白的细胞毒性因 hikeshi 缺失而增加。因此，Hikeshi 介导的 HSP70 的适当核质分布对于核蛋白稳态和对热休克的适应性反应是必需的。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5599/9113944/39533e5486f5/LSA-2021-01241_FigS7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5599/9113944/0d3fa53b711a/LSA-2021-01241_FigS1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5599/9113944/c6ef0effc1fe/LSA-2021-01241_Fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5599/9113944/7d478e1e0053/LSA-2021-01241_Fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5599/9113944/3bef30062866/LSA-2021-01241_FigS2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5599/9113944/d5bf4aebaaa8/LSA-2021-01241_FigS3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5599/9113944/5c1839813741/LSA-2021-01241_Fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5599/9113944/5b1074d1e840/LSA-2021-01241_FigS4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5599/9113944/ce7ad5409cd3/LSA-2021-01241_FigS5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5599/9113944/af081a00bec8/LSA-2021-01241_Fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5599/9113944/cf256364cc99/LSA-2021-01241_Fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5599/9113944/931b885b7bae/LSA-2021-01241_Fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5599/9113944/2f22519040ee/LSA-2021-01241_FigS6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5599/9113944/39533e5486f5/LSA-2021-01241_FigS7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5599/9113944/0d3fa53b711a/LSA-2021-01241_FigS1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5599/9113944/c6ef0effc1fe/LSA-2021-01241_Fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5599/9113944/7d478e1e0053/LSA-2021-01241_Fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5599/9113944/3bef30062866/LSA-2021-01241_FigS2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5599/9113944/d5bf4aebaaa8/LSA-2021-01241_FigS3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5599/9113944/5c1839813741/LSA-2021-01241_Fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5599/9113944/5b1074d1e840/LSA-2021-01241_FigS4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5599/9113944/ce7ad5409cd3/LSA-2021-01241_FigS5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5599/9113944/af081a00bec8/LSA-2021-01241_Fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5599/9113944/cf256364cc99/LSA-2021-01241_Fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5599/9113944/931b885b7bae/LSA-2021-01241_Fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5599/9113944/2f22519040ee/LSA-2021-01241_FigS6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5599/9113944/39533e5486f5/LSA-2021-01241_FigS7.jpg

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