RT Journal Article SR Electronic T1 Lack of Hikeshi activates HSF1 activity under normal conditions and disturbs the heat-shock response JF Life Science Alliance JO Life Sci. Alliance FD Life Science Alliance LLC SP e202101241 DO 10.26508/lsa.202101241 VO 5 IS 9 A1 Shingo Kose A1 Kenichiro Imai A1 Ai Watanabe A1 Akira Nakai A1 Yutaka Suzuki A1 Naoko Imamoto YR 2022 UL https://www.life-science-alliance.org/content/5/9/e202101241.abstract AB 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.