Nuclear translocation of hypoxia-inducible factors (HIFs): Involvement of the classical importin α/β pathway

Hypoxia-inducible factors are the key elements in the essential process of oxygen homeostasis of vertebrate cells. Stabilisation and subsequent nuclear localisation of HIF-α subunits results in the activation of target genes such as vegf, epo and glut1. The passage of transcription factors e.g. HIF-1α into the nucleus through the nuclear pore complex is regulated by nuclear transport receptors. Therefore nucleocytoplasmic shuttling can regulate transcriptional activity by facilitating the cellular traffic of transcription factors between both compartments. Here, we report on the identification of specific interactions of hypoxia-inducible factors with nuclear transport receptors importin α/β. HIF-1α, -1β, and HIF-2α are binding to importin α1, α3, α5, and α7. The direct interaction of HIF-1α to α importins is dependent on a functional nuclear localisation signal within the C-terminal region of the protein. In contrast, the supposed N-terminal NLS is not effective. Our findings provide new insight into the mechanism of the regulation of nuclear transport of hypoxia-inducible factors.