Hikeshi-flox Mouse

Hikeshi, also referred to as C11orf73, is a nonconventional nuclear import carrier of heat shock protein 70 family (HSP70s) [4]. It plays a crucial role in nucleocytoplasmic transport, which is essential for regulating cell physiology in eukaryotic cells [2]. Hikeshi-mediated nuclear translocation of HSP70s is involved in pathways related to cell differentiation, proteostasis, and the heat-shock response, and is of great biological importance [1,2,3]. Genetic models, such as gene knockout models, are valuable for studying Hikeshi's functions.

In inherited leukodystrophy patients, deficiency of Hikeshi leads to murine oligodendrocyte maturation arrest, demonstrating its essentiality for central nervous system (CNS) myelination [1]. Hikeshi-knockout cells show an up-regulation of genes regulated by HSF1 under non-stressed conditions and an impaired heat-shock response, suggesting that proper nucleocytoplasmic distribution of HSP70, mediated by Hikeshi, is required for nuclear proteostasis and adaptive response to heat shock [3]. In human oral squamous cell carcinoma HSC-3 cells and 22Rv1 cells (human castration-resistant prostate cancer cell line), Hikeshi silencing enhances the sensitivity to mild hyperthermia, as it inhibits the translocation of HSP70 from the cytoplasm to the nucleus under heat shock [4,5].

In conclusion, Hikeshi is vital for processes like CNS myelination, nuclear proteostasis, and the heat-shock response. Studies using Hikeshi KO models have provided insights into its role in diseases such as inherited leukodystrophy and in enhancing the effectiveness of hyperthermia in cancer treatment, highlighting its potential as a therapeutic target.