Nuclear localization of Hif-3α requires two redundant NLS motifs in its unique C-terminal region.

Hif-3 alpha, a member of the hypoxia-inducible factor (HIF) family, enters the nucleus and regulates gene expression in response to hypoxia. The molecular basis of its nuclear localization is not clear. HIF-1 alpha and HIF-2 alpha use a bipartite nuclear localization signal (NLS) to enter the nucleus. This motif is not conserved in Hif-3 alpha. Although there is a conserved Arg/Lys rich motif in the Hif-3 N-terminal region, deletion of this region has minimal effect on Hif-3 alpha nuclear localization. Here, we mapped the functional NLS to the unique C-terminal region of Hif-3 alpha and identified two clusters of basic residues critical for its nuclear localization. The two NLS motifs are functionally redundant. Our results, thus, suggest that Hif-3 alpha nuclear localization is mediated through two redundant NLS motifs located in its unique C-terminal region.