The N-terminal nuclear localization sequences of liver X receptors α and β bind to importin α and are essential for both nuclear import and transactivating functions

Liver X receptors (LXRs) α and β are nuclear receptors, which form obligate heterodimers with the retinoid X receptor (RXR). The LXRs regulate both redundantly and non-redundantly the transcription of genes controlling cholesterol metabolism and transport as well as lipogenesis. Previously, we showed that mutations in putative N-terminal nuclear localization sequences (NLSs) within both LXRs inhibit nuclear import. Through in vitro studies, we show here that these NLSs bind importin α and are both necessary and sufficient for the nuclear import of LXRs. Imaging, transactivation, and electro-mobility shift experiments show that RXR rescues the nuclear import of the LXRα NLS mutant yet does not restore its transcriptional activity despite intact DNA binding. In contrast, RXR partially rescues the import of the LXRβ NLS mutant, but has no effect on its transcriptional activity due to the loss of DNA binding. Experiments with NLS mutant RXR confirmed that RXR may dominate the nuclear import of the RXR/LXRα heterodimer, whereas LXRβ dominates the nuclear import of the RXR/LXRβ heterodimer. Intriguingly, our data indicate differences between LXRα and LXRβ in their interaction with RXR and in the role their NLSs play in transactivating functions independent of nuclear import.