Exportin 4 mediates a novel nuclear import pathway for Sox family transcription factors

Abstract

SRY and other Sox-type transcription factors are important developmental regulators with various implications in human disease. In this study, we identified Exp4 (exportin 4) as an interaction partner of Sox2 in mouse embryonic stem cells and neural progenitors. We show that, besides its established function in nuclear export, Exp4 acts as a bona fide nuclear import receptor for Sox2 and SRY. Thus, Exp4 is an example of a nuclear transport receptor carrying distinct cargoes into different directions. In contrast to a published study, we observed that the import activity of Imp-α (importin-a) isoforms toward Sox2 is negligible. Instead, we found that Imp9 and the Imp-β/7 heterodimer mediate nuclear import of Sox2 in parallel to Exp4. Import signals for the three pathways overlap and include conserved residues in the Sox2 high-mobility group (HMG) box domain that are also critical for DNA binding. This suggests that nuclear import of Sox proteins is facilitated by several parallel import pathways.

Landscape of nuclear transport receptor cargo specificity

“…For example, importin 13 (IPO13) has also been shown to have export capacity for the translation initiation factor elF1A (Mingot et al , 2001), and also exportin 4 (XPO4) has a bidirectional transport capability (Gontan et al , 2009). A specialized member of the importin β family is the cellular apoptosis susceptibility (CAS/XPO2) protein that is a recycling factor for importin αs (Kutay et al , 1997).…”

Esophageal cancer-related gene 4 is a secreted inducer of cell senescence expressed by aged CNS precursor cells

“…S7 C and D). Because the Olig1 and Sox2 localizations are regulated by nucleo-cytoplasmic shuttling under the control of importin and exportin (24,25), the shift of these transcription factors from the nucleus to the cytoplasm may reflect an age-dependent decline in nuclear pore activity (26)(27)(28). Moreover, we found that many cells in the CC (Fig.…”

Structure-Function Relationships in Human Testis-determining Factor SRY

“…5 Exp4 is a member of a class of proteins that mediate the export or import of cargo proteins (such as SRY) from the nucleus to the cytoplasm or from the cytoplasm to the nucleus. Although Exp4 was originally designated as an "exportin" in relation to its Ran-dependent role in the nuclear export of eukaryotic translational initiation factor 5A (94), Demmers and co-workers (47) have shown that Exp4 mediates nuclear import of SRY via interactions with the N-terminal segment of the HMG box (NLS residues 59 -77 in intact human SRY); an homologous interaction contributes to nuclear import of SOX9 (69). Nuclear exports of SRY and SOX9 are instead mediated by an interaction of CRM1 with a classical nuclear export signal (38,95 defects that together block SRY-directed transcriptional activation of Sox9.…”

“…This model enables dissection of distinct cellular processes (including TF expression, proteasome-mediated turnover, and nuclear import) underlying the operation of a sex-specific GRN. Because SRY functions as a nuclear protein (43)(44)(45)(46), effects of the substitutions were evaluated with respect to the machinery of nuclear import (candidate mediators Exportin-4 (Exp4 (47)) and calmodulin (CaM (48)). 5 Remarkably, our results have demonstrated that Trp-70 contributes to multiple biophysical properties and diverse biochemical activities of SRY.…”