Intrinsic and extrinsic negative regulators of nuclear protein transport processes

Abstract

The nuclear-cytoplasmic protein transport is a critical process in cellular events. The identification of transport signals (nuclear localization signal and nuclear export signal) and their receptors has facilitated our understanding of this expanding field. Nuclear transport must be appropriately regulated to deliver proteins through the nuclear pore when their functions are required in the nucleus, and to export them into the cytoplasm when they are not needed in the nucleus. Altered nuclear transport processes have been observed in stressed cells, which would change gene expressions. Some viruses interfere with nuclear transport in host cells to evade immune defense. Moreover, certain transport factors negatively regulate nuclear protein transport in cells. Understanding the regulatory mechanisms of nuclear-cytoplasmic trafficking not only provides important information about cellular processes, but also is of use for developing specific inhibitors for transport pathways.

Figure 1

Active nuclear–cytoplasmic transport of proteins. The cargo proteins containing a nuclear localization signal (NLS) are recognized by importin βs alone or importin α/β1 heterodimer, whereas cargo proteins that possess a nuclear export signal (NES) bind to exportins in the presence of Ran-GTP. The transport complexes pass through nuclear pores by sequential and transient interaction of importin β with Nups within the NPC. Within the nucleus, Ran-GTP binding to importin β dissociates the import complex. Ran-GTP to Ran-GDP exchange facilitated by RanBP1 and RanGAP1 dissociates the nuclear export complex in the cytoplasm. Ran-GDP is converted to the GTP-bound form by RCC1 in the nucleus.

Figure 2

Schematic representation of the mammalian NPC. The relative position of various Nups is listed. The Nups altered by cellular stresses and virus infection are indicated in blue and yellow, respectively.

Figure 3

Some viruses and protozoans inhibit the nuclear–cytoplasmic protein trafficking of the host cell. The nuclear import of immune response factors such as Stat1 and NFκB is the target of certain viruses and protozoans. VEEV H68 inhibits both importin α/β1-mediated nuclear import and CRM1-dependent nuclear export pathways. Transportin- and importin 5-mediated nuclear imports are impaired by HPV L1 protein.

Figure 4

Importin α acts as a negative regulator for the nuclear import of certain proteins. TRF1 and Snail are transported into the nucleus by the importin β1-mediated pathway. In the presence of importin α, TRF1 forms a complex with importin α/β1 heterodimer by binding to importin β1, but this complex remains in the cytoplasm. In contrast, importin α competes with the binding of importin β1 to Snail zinc finger domain, resulting in the inefficient nuclear accumulation of Snail. S-nitrosylation of CRM1 by NO inhibits its binding to NES-containing cargos.