Nuclear Trafficking in Health and Disease

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In eukaryotic cells, the cytoplasm and the nucleus are separated by a double-membraned nuclear envelope (NE). Thus, transport of molecules between the nucleus and the cytoplasm occurs via gateways termed the nuclear pore complexes (NPCs), which are the largest intracellular channels in nature. While small molecules can passively translocate through the NPC, large molecules are actively imported into the nucleus by interacting with receptors that bind nuclear pore complex proteins (Nups). Regulatory factors then function in assembly and disassembly of transport complexes. Signaling pathways, cell cycle, pathogens, and other physiopathological conditions regulate various constituents of the nuclear transport machinery. Here, we will discuss several findings related to modulation of nuclear transport during physiological and pathological conditions, including tumorigenesis, viral infection, and congenital syndrome. We will also explore chemical biological approaches that are being used as probes to reveal new mechanisms that regulate nucleocytoplasmic trafficking and that are serving as starting points for drug development.

Section snippets

Nuclear transport in health

Transport of molecules of less than 50 kDa can passively occur through the NPC. However large molecules, including proteins, require receptors for trafficking through the NPC. Proteins usually contain specific motifs termed nuclear localization sequences (NLSs) and nuclear export sequences (NESs) that are recognized by transport receptors termed karyopherins, importins (α and β transportin, snurportin, etc.), or exportins (Crm1/XPO/exportin 1, etc.). The receptor–cargo complexes interact with

Nucleocytoplasmic trafficking in cell proliferation and tumorigenesis

An elegant mode for regulation of nuclear transport is achieved by post-translation modifications [5]. An example of such regulation can be found in the NF-κB signaling pathway, a major regulator of immunity and cell proliferation, which is involved in tumorigenesis and response to viral infection [6]. Briefly, in basal conditions, NF-κB binds to its inhibitory protein IκB. Since IκB masks the NF-κB NLS, this heterodimer is mostly cytoplasmic. As a response to stress or extracellular cues

Nucleoporin action in stress and oncogenesis outside the NPC

Aside from nucleocytoplasmic transport, it has been shown that some nucleoporins have additional functions inside the nucleus, some of which are directly related to development, stress, and tumorigenesis. One example is Nup98 that shuttles between the NPC and the nucleoplasm and regulates transcription of subsets of genes involved in development and cell cycle [31, 32]. In addition, chromosomal translocations that lead to fusion proteins between Nup98 and transcription factors are known to be

mRNA export in viral infection and metabolism

Many viruses, including cytoplasmic replicating or nuclear replicating viruses, have been shown to target the nuclear transport machinery (for a complete review please see Refs [45, 46]). Regulation of the nuclear transport machinery can facilitate major proviral outcomes: reduce competition with host factors for gene expression and prevent host antiviral responses. In some cases it was demonstrated that the upregulation of the nuclear transport machinery promotes antiviral response. One

mRNA export in congenital contracture syndrome

Another interesting disease related to defect in mRNA export is human lethal congenital contracture syndrome-1 (LCCS1). It is caused by a proline–phenylalanine–glutamine peptide insertion in the coiled-coil domain of Gle1 [55], a key mRNA export factor. As mentioned above, Gle1 functions in mRNA export as an important regulator of the RNA-dependent ATPase activity of Dbp5, which mediates the key step for mRNA release at the cytoplasmic side of the NPC [3]. Disruption of Dbp5 function leads to

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

We thank Angela Diehl for outstanding figure design. This work was supported by NIH R01AI079110, R01AI089539 and CPRIT RP121003-RP120718-P2.

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