Small molecules, such as ions, can pass through the nucleus with ease. However, cargo proteins and RNAs that need to be transported require importins and exportins to enter and exit the nucleus, respectively.
On one hand, the cargo binds with the importin in the cytoplasm, and then moved into the nucleus through the nuclear pore. On the other hand, the cargo binds with the exportin inside the nucleus, and then moved outside the nucleus via the nuclear pore. Nuclear transport needs energy to proceed. Thus, GTPases e. Ran enzyme help by hydrolyzing GTP guanosine triphosphate so that energy would be released in the process.
The energy released would be used to dissociate the cargo from the importins and to bind the cargo to the exportins. The nuclear envelope compartmentalizes the nucleoplasm, setting boundaries between the nucleus and the cytoplasm. Nevertheless, it is perforated with holes called nuclear pores that regulate the exchange of substances for example, proteins and RNA between the nucleus and the cytoplasm.
The nuclear transport of the large molecules like proteins and RNAs occurs via an active transport system carrier proteins while the passage of small molecules and ions occur passively via the nuclear pores. Plant cells have plastids essential in photosynthesis. They also have an additional layer called cell wall on their cell exterior. Although animal cells lack these cell structures, both of them have nucleus, mitochondria, endoplasmic reticulum, etc.
Research 23 June Open Access. Reviews 08 February Karoutas and Akhtar review the roles of the nuclear lamina in chromatin-related functions, including transcription, epigenetic regulation and chromatin architecture, and their abnormalities in diseases and ageing.
Research 27 January Research 04 December Open Access. Mechanical strength of in situ assembled nuclear lamin filaments arranged in a 3D meshwork is unclear. Research Highlights 20 July Vietri et al. Research Highlights 23 October Correspondence 18 September Open Access. Research Highlights 29 June Structural support is provided to the nuclear envelope by two different networks of intermediate filaments. Along the inner surface of the nucleus, one of these networks is organized into a special mesh-like lining called the nuclear lamina , which binds to chromatin, integral membrane proteins, and other nuclear components.
The nuclear lamina is also thought play a role in directing materials inside the nucleus toward the nuclear pores for export and in the disintegration of the nuclear envelope during cell division and its subsequent reformation at the end of the process. The other intermediate filament network is located on the outside of the outer nuclear membrane and is not organized in such a systemic way as the nuclear lamina.
The amount of traffic that must pass through the nuclear envelope on a continuous basis in order for the eukaryotic cell to function properly is considerable. RNA and ribosomal subunits must be constantly transferred from the nucleus where they are made to the cytoplasm, and histones, gene regulatory proteins, DNA and RNA polymerases, and other substances required for nuclear activities must be imported from the cytoplasm.
An active mammalian cell can synthesize about 20, ribosome subunits per minute, and at certain points in the cell cycle, as many as 30, histones per minute are required by the nucleus.
In order for such a tremendous number of molecules to pass through the nuclear envelope in a timely manner, the nuclear pores must be highly efficient at selectively allowing the passage of materials to and from the nucleus. License Info. In addition, fibroblasts derived from lamina-null mouse embryos showed an impaired mechanically activated gene transcription Crisp et al. Structural and gene regulation hypotheses are not mutually exclusive and could be interrelated by nuclear mechanotransduction Wang et al.
For instance, Hutchinson-Gilford progeria syndrome nuclei do induce an altered shear stress response, while they also show changes in gene expression Philip and Dahl, ; Wang et al. Thus, changes in nuclear structure and function could contribute both to increased cellular sensitivity to mechanical strain and to altered transcriptional regulation Wang et al.
Laminopathic diseases such as familial partial lipodystrophy of the Dunningan type and Emery-Dreifuss muscular dystrophy indeed show lamin A mutation in the Ig-fold domain, where the lamins are assumed to be connected to the basket Nup This suggests that Nup has a role in the etiology of laminopathies Al-Haboubi et al. In addition, it has been noted that mutations in the LMNA gene correlate with a decrease in Nup at the nuclear envelope Duheron and Fahrenkrog, Alterations in lamin A and C imply an impaired mechanoresistance of the nuclear lamina with consequent alteration in mechanotransduction from the LINC complex Philip and Dahl, ; Miroshnikova et al.
Here we suggest that a defective mechanotransduction can induce an alteration in basket opening, causing both impairment in the transport of molecules through the NPC and changes in chromatin organization. Supporting this hypothesis, studies have revealed that lamin A alteration has an impact on both the localization and distribution of NPC proteins implicated in molecular transport and on the decreased import pathway Busch et al.
Again, other evidence shows that the altered protein import is associated with Hutchinson-Gilford progeria syndrome, restrictive dermopathy and aging Busch et al. Altered mechanotransduction may also be due to the destruction of LINC complexes, which could be the cause of other laminopathies such as Emery-Dreifuss muscular dystrophy and dilated cardiomyopathy, and neural disorders such as lissencephalites Stewart-Hutchinson et al.
LINC destruction can cause impaired force transmission to the nuclear basket, and basket molecular structures, such as Nup and Tpr, are likely to be the primary cause of laminopathies. In addition to laminopathies, deregulated lamin expression has been observed in several cancers Matsumoto et al.
Loss of lamin A and C expression has been revealed in colon cancer, breast cancer, small cell lung cancer, leukaemias and lymphomas. In contrast, the overexpression of lamin A and C has been reported in skin cancer, colorectal cancer, and prostate cancer Matsumoto et al. Although the precise functions of reduced LINC complex remain elusive, it has been suggested that the loss of LINC complex SUN1, SUN2, Nesprin2 might alter nuclear structure and mechanical properties, affecting genome integrity, proliferation, and cell migration with consequences for cancer progression, and may induce impairment in DNA repair, which plays a role in tumor initiation Matsumoto et al.
Table 1. Table 2. Several studies investigated nuclear involvement in the cell mechanotransduction and cell fate but only in recent years the research has been trying to correlate this mechanism with the architecture and function of the NPCs.
Several aspects remain so far elusive. Based on the literature, we summarized the main experimental evidence and proposed models showing a mechanosensing role of the NPC and its relationship with several pathologies. We hypothesize that the nuclear basket has a key role as the primary regulator of NPC transport, by means of a mechanoactivation mechanism involving SUN1 and Nup proteins.
Our group is further exploring the possibility of verifying the behavior of the nuclear basket as a stretch-gated structure, using biophysical and computational methods. Specifically, we are investigating the molecular arrangement of the NupSUN1 complex through molecular dynamic studies based on homology modeling predictions, and with X-ray crystallography techniques. At a broader level, we plan to develop a model to evaluate external force transmission and its effects on the nuclear pore complex structure.
This engineering approach should lead to a more quantitative understanding of basket structure alteration and its potential effect on transcription and disease. All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Agaram, N. Recurrent NTRK1 gene fusions define a novel subset of locally aggressive lipofibromatosis-like neural tumors. Agudo, D. Nup88 mRNA overexpression is associated with high aggressiveness of breast cancer. Cancer , — Alber, F. The molecular architecture of the nuclear pore complex. Nature , — Al-Haboubi, T.
Distinct association of the nuclear pore protein Nup with A- and B-type lamins. Nucleus 2, — Au, S. Nuclear transport of baculovirus: revealing the nuclear pore complex passage. Ball, J. Versatility at the nuclear pore complex: lessons learned from the nucleoporin Nup Chromosoma , — Basel-vanagaite, L.
Mutated nup62 causes autosomal recessive infantile bilateral striatal necrosis. Bootman, M. An update on nuclear calcium signalling. Cell Sci. Braun, D. Broers, J. Nuclear A-type lamins are differentially expressed in human lung cancer subtypes.
Busch, A. Nuclear protein import is reduced in cells expressing nuclear envelopathy-causing lamin A mutants. Cell Res. Byrd, D. Tpr, a large coiled coil protein whose amino terminus is involved in activation of oncogenic kinases, is localized to the cytoplasmic surface of the nuclear pore complex. Cell Biol. Capelson, M. Chromatin-bound nuclear pore components regulate gene expression in higher eukaryotes.
Cell , — Chen, C. Accumulation of the inner nuclear envelope protein Sun1 is pathogenic in progeric and dystrophic laminopathies. Chen, L. Lancet , — Chen, Z. Dysregulated interactions between lamin A and SUN1 induce abnormalities in the nuclear envelope and endoplasmic reticulum in progeric laminopathies. Chi, Y. Reversal of laminopathies: the curious case of SUN1. Nucleus 3, — Choi, Y. Chug, H. Crystal structure of the metazoan Nup62Nup58Nup54 nucleoporin complex.
Science , — Crisp, M. Coupling of the nucleus and cytoplasm: role of the LINC complex. Cronshaw, J. PNAS , — De Sandre-giovannoli, A. Del Viso, F. Congenital heart disease genetics uncovers context-dependent organization and function of nucleoporins at cilia.
Cell 38, — Duheron, V. Structural characterization of altered nucleoporin Nup expression in human cells by thin-section electron microscopy. Nucleus 5, — The nuclear pore complex: structure and function. Atlas Genet. Eibauer, M. Supplementary structure and gating of the nuclear pore complex. Elosegui-Artola, A. Force triggers YAP nuclear entry by regulating transport across nuclear pores.
Frey, S. EMBO J. FG-rich repeats of nuclear pore proteins form a three-dimensional meshwork with hydrogel-like properties. PubMed Abstract Google Scholar. Fujitomo, T. Critical function for nuclear envelope protein TMEM in human pulmonary carcinogenesis. Cancer Res. Gamini, R. Assembly of Nsp1 nucleoporins provides insight into nuclear pore complex gating. PLoS Comput. The effect of cell morphology on the permeability of the nuclear envelope to diffusive factors.
Modeling of the mechano-chemical behaviour of the nuclear pore complex: current research and perspectives. Gay, S. Nuclear envelope and chromatin, lock and key of genome integrity. Cell Mol.
Ghavami, A. Probing the disordered domain of the nuclear pore complex through coarse-grained molecular dynamics simulations-SI. Goldberg, M. Nuclear pore complex tethers to the cytoskeleton. Cell Dev.
0コメント