Nucleocytoplasmic Transport
Nucleocytoplasmic transport is central to the functioning of eukaryotic cells and is an integral part of the processes that lead to most human diseases. We have elucidated the molecular basis for recognition of classical import substrates by the transport receptor importin-b (Figure 1). Importin b is the prototype of a family of transport factors ubiquitously found in all eukaryotic cells. Together with the adaptor importin a, importin b mediates nuclear import of proteins bearing a classical Nuclear Localization Signal (NLS), exemplified by the SV40 large T antigen NLS (126PKKKRRV132).
In addition to the classical importin a/b-dependent nuclear import pathway, eukaryotic cells have developed a remarkable variety of alternative import pathways, also referred as non-classical Alternative import pathways often rely on distinct non-classical transport signals, and use diverse mechanisms of import.
In my laboratory, we investigate the molecular basis for the recognition and nuclear import of three non-classical cargos, which include the small nuclear ribonucleoprotein (snRNP) transporter snurportin, the HIV-1 Rev protein, and the transcription factor STAT1. Our work is aimed at understanding:
- how non-classical NLSs are structurally recognized by importin a and b,
- how the nuclear import reaction is regulated, both in terms of energy requirement and kinetic of accumulation into the nucleus,
- the role of phosphorilation in the activation and regulation of non-classical NLSs.
Our research on non-classical NLS is important to understand how living cells regulate the availability of essential factors bearing nuclear activity (e.g. transcription factors, DNA replication factors, etc). This is emerging as a novel and very powerful way to control gene expression and cellular differentiation. Likewise, misregulation of nuclear transport both in over-proliferating tumor cells and in cells hijacked by pathogenic viruses, is emerging as a critically important target for pharmacological intervention.