Hikeshi modulates the proteotoxic stress response in human cells: Implication for the importance of the nuclear function of <scp>HSP</scp>70s

Rahman, Khondoker Md Zulfiker; Mamada, Hiroshi; Takagi, Motoki; Kose, Shingo; Imamoto, Naoko

doi:10.1111/gtc.12536

Cited by 8 publications

(11 citation statements)

References 42 publications

(53 reference statements)

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“…In line with previous reports (30)(31)(32), our experiments demonstrated that HIKESHI-Kd did not affect the number of viable cells under normal conditions at 37˚C, suggesting that HIKESHI may not be required for the normal growth of OSCC HSC-3 cells. Interestingly, HIKESHI silencing significantly enhanced MHT sensitivity of HSc-3 cells, as demonstrated by the cell viability assay.…”

Section: Discussionsupporting

confidence: 92%

“…Interestingly, HIKESHI silencing significantly enhanced MHT sensitivity of HSc-3 cells, as demonstrated by the cell viability assay. These results were comparable to those of previous studies (30)(31)(32). Immunocytochemical analysis clearly demonstrated that HIKESHI-Kd effectively prevented the nuclear translocation of Hsp70.…”

Section: Discussionsupporting

confidence: 90%

“…Kose et al (30) reported for the first time that the nuclear import of Hsp70 is mediated by the heat shock protein nuclear import factor hikeshi (HIKESHI), also referred to as c11orf73, under conditions of heat-induced stress. Although silencing of HIKESHI had no discernible effect under normal conditions, it was found to significantly inhibit the nuclear translocation of Hsp70 or to reduce cell viability after exposure of cancer cells to heat stress (30)(31)(32).…”

Section: Introductionmentioning

confidence: 91%

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HIKESHI silencing can enhance mild hyperthermia sensitivity in human oral squamous cell carcinoma HSC‑3 cells

et al. 2020

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Hyperthermia (HT) is considered to be of value as a treatment modality in various cancers. However, the acquisition of thermotolerance in cancer cells due to the induction of heat shock proteins (HSPs) makes HT less effective. Recent findings have indicated that heat shock protein nuclear import factor hikeshi (HIKESHI), also referred to as c11orf73, acts as a nuclear import carrier of Hsp70 under heat stress conditions. The aim of the present study was to determine whether knockdown (Kd) of HIKESHI by small interfering RNA (siRNA) can potentiate mild HT (MHT) sensitivity in human oral squamous cell carcinoma (OScc) HSc-3 cells. The mRNA and protein expression of HIKESHI was found to be markedly suppressed in HSc-3 cells treated with siRNA for HIKESHI (siHIKE). Silencing HIKESHI significantly decreased the cell viability under MHT conditions (42˚C for 90 min). Immunocytochemical and western blot analyses clearly demonstrated that Hsp70 protein translocated from the cytoplasm to the nucleus under MHT conditions, and this translocation was significantly inhibited in cells treated with siHIKE. Treatment of the cells with MHT transiently increased the phosphorylation level of extracellular signal-regulated kinase (ERK)2. Furthermore, the phosphorylation was sustained in HIKESHI-Kd cells under MHT conditions, and this sustained phosphorylation was abolished by pretreatment with U0126, an inhibitor of mitogen-activated protein kinase/ERK. In addition, U0126 significantly decreased the viability of cells treated with the combination of HIKESHI-Kd and MHT. The data of the present study suggest that HIKESHI silencing enhanced the sensitivity of human OScc HSc-3 cells to MHT.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 90%

Section: Introductionmentioning

confidence: 91%

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HIKESHI silencing can enhance mild hyperthermia sensitivity in human oral squamous cell carcinoma HSC‑3 cells

et al. 2020

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“…We initially showed that Hikeshi is required for cell survival after heat shock (acute heat stress) (Kose et al, 2012), but our subsequent studies showed that the effect of Hikeshi is more complicated (Rahman et al, 2017). Depletion of Hikeshi reduced the survival of HeLa cells but increased the survival of hTERT-RPE1 cells in response to proteotoxic stress.…”

Section: Ko Of the Hikeshi Gene Induces A Reduction In Nuclear Hsp70 ...mentioning

confidence: 99%

“…Currently, in humans, Hikeshi is the only carrier molecule of HSP70s for nuclear import. Dysfunction of Hikeshi inhibits the nuclear import of HSP70s under heat-shock conditions and then impairs recovery of the cell from stress damage, leading to cell death or aberrant cell growth (Kose et al, 2012;Rahman et al, 2017;Yanoma et al, 2017). Exogenously expressed classical NLStagged HSP70, which is carried into the nucleus by the importin-α/β pathway, significantly suppresses cell death of Hikeshi-depleted HeLa cells caused by heat shock (Kose et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2022

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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.

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Heat stress-induced nuclear transport mediated by Hikeshi confers nuclear function of Hsp70s

Imamoto

2018

Current Opinion in Cell Biology

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The prime feature of eukaryotic cells is the separation of the intracellular space into two compartments, the nucleus and the cytoplasm. Active nuclear transport is crucial for the maintenance of this separation. In this report, we focus on a nuclear transport receptor named Hikeshi, which mediates the heat stress-induced nuclear import of 70-kDa heat shock proteins (Hsp70s), and discuss how the same protein can function differently depending on the cellular compartment in which it is localized. Hsp70 is a molecular chaperone that is predominantly localized in the cytoplasm under normal conditions but is known to accumulate in the nucleus under conditions of heat stress. Although the reported function of Hsp70 is mostly attributed to its molecular function in the cytoplasm, the functions of Hsp70 may extend beyond molecular chaperone activity in the nucleus.

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Hikeshi modulates the proteotoxic stress response in human cells: Implication for the importance of the nuclear function of HSP70s

Cited by 8 publications

References 42 publications

HIKESHI silencing can enhance mild hyperthermia sensitivity in human oral squamous cell carcinoma HSC‑3 cells

HIKESHI silencing can enhance mild hyperthermia sensitivity in human oral squamous cell carcinoma HSC‑3 cells

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

Heat stress-induced nuclear transport mediated by Hikeshi confers nuclear function of Hsp70s

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