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

Area of Science:

• Molecular Biology
• Cell Biology
• Developmental Biology

Background:

• Sox transcription factors, including Sox2 and SRY, are crucial for development and implicated in diseases.
• Nuclear transport receptors regulate the movement of proteins into and out of the cell nucleus.

Purpose of the Study:

• To identify novel interaction partners and nuclear transport mechanisms for Sox2.
• To elucidate the role of exportin 4 (Exp4) in Sox2 nuclear import.

Main Methods:

• Co-immunoprecipitation to identify interaction partners of Sox2.
• Nuclear import assays in cellulo to assess the function of transport receptors.
• Site-directed mutagenesis to map nuclear import signals within Sox2.

Main Results:

• Exportin 4 (Exp4) was identified as a novel interaction partner of Sox2 in mouse embryonic stem cells and neural progenitors.
• Exp4 functions as a nuclear import receptor for Sox2 and SRY, in addition to its known nuclear export roles.
• Importin-alpha isoforms showed negligible import activity for Sox2; instead, Imp9 and the Imp-beta/7 heterodimer mediate parallel nuclear import pathways for Sox2.
• Nuclear import signals for these pathways overlap and reside within the DNA-binding high-mobility group (HMG) box domain of Sox2.

Conclusions:

• Sox2 and SRY nuclear import is facilitated by multiple parallel pathways, including Exp4, Imp9, and Imp-beta/7.
• Exp4 acts as a unique nuclear transport receptor, mediating both import and export of different cargoes.
• The findings reveal a complex regulatory mechanism for Sox protein nuclear localization critical for their developmental functions.