{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n HIKESHI is a novel and evolutionarily conserved nuclear transport receptor that plays a central role in cellular thermotolerance by mediating the heat stress–induced nuclear import of 70‐kDa heat shock proteins (Hsp70s)."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " Unlike the canonical importin‐β pathways that depend on the small GTPase Ran, HIKESHI functions independently by directly interacting with FG‐nucleoporins, thus enabling the ATP‐bound form of Hsp70 to translocate into the nucleus during thermal stress."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": " This nuclear entry of Hsp70 is essential for attenuating and reversing multiple stress‐induced nuclear phenotypes, thereby protecting cells from proteotoxic damage."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In addition to its basic cellular function, structural studies have revealed that HIKESHI adopts an asymmetric homodimeric conformation with distinct domains that mediate its interactions both with Hsp70 and with nuclear pore FG repeats."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": " Dysfunction or depletion of HIKESHI impairs the nuclear import of Hsp70, exacerbating stress responses and reducing cell viability under heat shock or proteotoxic stress conditions."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": " Notably, inhibition of HIKESHI has been shown to potentiate the effects of hyperthermia in cancer models such as oral squamous cell carcinoma and gastric cancer, suggesting that targeting HIKESHI might enhance the efficacy of hyperthermia‐based therapies."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Moreover, genetic studies have demonstrated that mutations in HIKESHI are linked to congenital disorders characterized by hypomyelinating leukodystrophies and leukoencephalopathies, underscoring its importance in neural protection and myelin maintenance."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "7", "end_ref": "9"}]}, {"type": "t", "text": " In parallel, studies in plant systems have identified HIKESHI‐like proteins that similarly regulate the nuclear localization of Hsp70 isoforms to confer thermotolerance, indicating that the mechanism is broadly conserved across eukaryotes."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Collectively, these findings establish HIKESHI as a critical mediator of the cellular stress response that preserves nuclear proteostasis, modulates heat shock signaling, and influences disease outcomes ranging from cancer progression to neurodevelopmental disorders."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}, {"type": "fg_f", "ref": "7"}, {"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": " \n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Shingo Kose, Maiko Furuta, Naoko Imamoto "}, {"type": "b", "children": [{"type": "t", "text": "Hikeshi, a nuclear import carrier for Hsp70s, protects cells from heat shock-induced nuclear damage."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.cell.2012.02.058"}], "href": "https://doi.org/10.1016/j.cell.2012.02.058"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22541429"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22541429"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Jinsue Song, Shingo Kose, Ai Watanabe, et al. 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