Hikeshi, a Nuclear Import Carrier for Hsp70s, Protects Cells from Heat Shock-Induced Nuclear Damage

• Published in: Cell 2012-04, Vol.149 (3), p.578-589
• Main Authors: Kose, Shingo, Furuta, Maiko, Imamoto, Naoko
• Format: Article
• Language: English
• Subjects: Active Transport, Cell Nucleus; adenosine diphosphate; adenosine triphosphate; adenosinetriphosphatase; Amino Acid Sequence; Animals; Carrier Proteins - chemistry; Carrier Proteins - genetics; Carrier Proteins - isolation & purification; Carrier Proteins - metabolism; Cell Nucleus - metabolism; cell viability; heat; Heat-Shock Response; HeLa Cells; HSP70 Heat-Shock Proteins - metabolism; Humans; importins; molecular chaperones; Molecular Chaperones - metabolism; Molecular Sequence Data; Nuclear Pore - metabolism; nucleocytoplasmic transport; phenotype; Sequence Alignment
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2012.02.058

During heat shock stress, importin β family-mediated nucleocytoplasmic trafficking is downregulated, whereas nuclear import of the molecular chaperone Hsp70s is upregulated. Here, we identify a nuclear import pathway that operates during heat shock stress and is mediated by an evolutionarily conserved protein named “Hikeshi,” which does not belong to the importin β family. Hikeshi binds to FG-Nups and translocates through nuclear pores on its own, showing characteristic features of nuclear transport carriers. In reconstituted transport, Hikeshi supports the nuclear import of the ATP form of Hsp70s, but not the ADP form, indicating the importance of the Hsp70 ATPase cycle in the import cycle. In living cells, depletion of Hikeshi inhibits heat shock-induced nuclear import of Hsp70s, reduces cell viability after heat shock stress, and significantly delays the attenuation and reversion of multiple heat shock-induced nuclear phenotypes. Nuclear Hsp70s rescue the effect of Hikeshi depletion at least in part. Thus, Hsp70s counteract heat shock-induced damage by acting inside of the nucleus. [Display omitted] ▸ Hikeshi is a nuclear import carrier for Hsp70s that operates during heat shock stress ▸ Hikeshi binds directly to ATP-Hsp70s and dissociates preferentially from ADP-Hsp70s ▸ Hikeshi attenuates and reverses heat shock-induced nuclear phenotypes ▸ Hsp70s counteract heat shock stress damage by acting inside of the nucleus Hikeshi transports Hsp70 family proteins into the nucleus during heat shock, defining a new import pathway that functions under conditions when importin β-dependent traffic declines.