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Components and regulation of nuclear transport processes.

ABSTRACT: The spatial separation of DNA replication and gene transcription in the nucleus and protein translation in the cytoplasm is a uniform principle of eukaryotic cells. This compartmentalization imposes a requirement for a transport network of macromolecules to shuttle these components in and out of the nucleus. This nucleo-cytoplasmic transport of macromolecules is critical for both cell physiology and pathology. Consequently, investigating its regulation and disease-associated alterations can reveal novel therapeutic approaches to fight human diseases, such as cancer or viral infection. The characterization of the nuclear pore complex, the identification of transport signals and transport receptors, as well as the characterization of the Ran system (providing the energy source for efficient cargo transport) has greatly facilitated our understanding of the components, mechanisms and regulation of the nucleo-cytoplasmic transport of proteins in our cells. Here we review this knowledge with a specific emphasis on the selection of disease-relevant molecular targets for potential therapeutic intervention.

SUBMITTER: Cautain B

PROVIDER: S-EPMC7163960 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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Components and regulation of nuclear transport processes.

Cautain Bastien B Hill Richard R de Pedro Nuria N Link Wolfgang W

The FEBS journal 20141222 3

The spatial separation of DNA replication and gene transcription in the nucleus and protein translation in the cytoplasm is a uniform principle of eukaryotic cells. This compartmentalization imposes a requirement for a transport network of macromolecules to shuttle these components in and out of the nucleus. This nucleo-cytoplasmic transport of macromolecules is critical for both cell physiology and pathology. Consequently, investigating its regulation and disease-associated alterations can reve ...[more]

PMID: 25429850

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Project description:BackgroundImportin-α1 belongs to a subfamily of nuclear transport adaptors and participates in diverse cellular functions. Best understood for its role in protein transport, importin-α1 also contributes to other biological processes. For instance, arsenite treatment causes importin-α1 to associate with cytoplasmic stress granules (SGs) in mammalian cells. These stress-induced compartments contain translationally arrested mRNAs, small ribosomal subunits and numerous proteins involved in mRNA transport and metabolism. At present, it is not known whether members of all three importin-α subfamilies locate to SGs in response to stress.ResultsHere, we demonstrate that the oxidant diethyl maleate (DEM), arsenite and heat shock, promote the formation of cytoplasmic SGs that contain nuclear transport factors. Specifically, importin-α1, α4 and α5, which belong to distinct subfamilies, and importin-β1 were targeted by all of these stressors to cytoplasmic SGs, but not to P-bodies. Importin-α family members have been implicated in transcriptional regulation, which prompted us to analyze their ability to interact with poly(A)-RNA in growing cells. Our studies show that importin-α1, but not α4, α5, importin-β1 or CAS, associated with poly(A)-RNA under nonstress conditions. Notably, this interaction was significantly reduced when cells were treated with DEM. Additional studies suggest that importin-α1 is likely connected to poly(A)-RNA through an indirect interaction, as the adaptor did not bind homopolymer RNA specifically in vitro.SignificanceOur studies establish that members of three importin-α subfamilies are bona fide SG components under different stress conditions. Furthermore, importin-α1 is unique in its ability to interact with poly(A)-RNA in a stress-dependent fashion, and in vitro experiments indicate that this association is indirect. Collectively, our data emphasize that nuclear transport factors participate in a growing number of cellular activities that are modulated by stress.

Project description:Radioactive gas signatures from underground nuclear explosions (UNEs) result from gas-migration processes occurring in the subsurface. The processes considered in this study either drive or retard upward migration of gases from the detonation cavity. The relative importance of these processes is evaluated by simulating subsurface transport in a dual-permeability medium for the multi-tracer Noble Gas Migration Experiment (NGME) originally intended to study some aspects of transport from a UNE. For this experiment, relevant driving processes include weak two-phase convection driven by the geothermal gradient, over pressuring of the detonation cavity, and barometric pumping while gas sorption, dissolution, radioactive decay, and usually diffusion represent retarding processes. From deterministic simulations we found that over-pressuring of the post-detonation chimney coupled with barometric pumping produced a synergistic effect amplifying the tracer-gas reaching the surface. Bounding simulations indicated that the sorption and dissolution of gases, tending to retard transport, were much smaller than anticipated by earlier laboratory studies. The NGME observations themselves show that differences in gas diffusivity have a larger effect on influencing upward transport than do the combined effects of tracer-gas sorption and dissolution, which is consistent with a Sobol' sensitivity analysis. Both deterministic simulations and those considering parametric uncertainties of transport-related properties predict that the excess in concentration of SF[Formula: see text] compared to [Formula: see text]Xe as might be captured in small volumetric samples should be much smaller than the order-of-magnitude contrast found in the large-volume gas samples taken at the site. While extraction of large-volume subsurface gas samples is shown to be capable of distorting in situ gas compositions, the highly variable injection rate of SF[Formula: see text] into the detonation cavity relative to that of [Formula: see text]Xe at the start of the field experiment is the most likely explanation for the large difference in observed concentrations.

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Components and regulation of nuclear transport processes.

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Components and regulation of nuclear transport processes.

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