BACKGROUND: Nuclear pore complexes (NPCs) are the architectures entrenched in nuclear envelop of a cell that regulate the nucleo-cytoplasmic transportation of materials, such as proteins and RNAs for proper functioning of a cell. The appropriate localization of proteins and RNAs within the cell is essential for its normal functionality. For such a complex transportation of materials across the NPC, around 60 proteins are involved comprising nucleoporins, karyopherins and RAN system proteins that play a vital role in NPC\'s structure formation, cargo translocation across NPC, and cargoes\' rapid directed transportation respectively. In various cancers, the structure and function of NPC is often exaggerated, following altered expressions of its nucleoporins and karyopherins, affecting other proteins of associated signaling pathways. Some inhibitors of karyopherins at present, have potential to regulate the altered level/expression of these karyopherin molecules.
OBJECTIVE: This review summarizes the data from 1990 to 2023, mainly focusing on recent studies that illustrate the structure and function of NPC, the relationship and mechanisms of nucleoporins and karyopherins with colorectal cancer, as well as therapeutic values, in order to understand the pathology and underlying basis of colorectal cancer associated with NPC. This is the first review to our knowledge elucidating the detailed updated studies targeting colorectal cancer at NPC. The review also aims to target certain karyopherins, Nups and their possible inhibitors and activators molecules as a therapeutic strategy.
UNASSIGNED: NPC structure provides understanding, how nucleoporins and karyopherins as key molecules are responsible for appropriate nucleocytoplasmic transportation. Many studies provide evidences, describing the role of disrupted nucleoporins and karyopherins not only in CRC but also in other non-hematological and hematological malignancies. At present, some inhibitors of karyopherins have therapeutic potential for CRC, however development of more potent inhibitors may provide more effective therapeutic strategies for CRC in near future.

Accurate nucleocytoplasmic transport of signal molecules is essential for plant growth and development. Multiple studies have confirmed that nucleocytoplasmic transport and receptors are involved in regulating plant disease resistance responses, however, little is known about the regulatory mechanism in plants. In this study, we showed that the mutant of the importin beta-like protein SAD2 exhibited a more susceptible phenotype than wild-type Col-0 after treatment with Pseudomonas syringae pv tomato DC3000 (Pst DC3000). Coimmunoprecipitation (Co-IP) and bimolecular fluorescence complementation (BiFC) experiments demonstrated that SAD2 interacts with the hypersensitive response (HR)-positive transcriptional regulator MYB30. Subcellular localization showed that MYB30 was not fully localized in the nucleus in sad2-5 mutants, and western-blot experiments further indicated that SAD2 was required for MYB30 nuclear trafficking during the pathogen infection process. A phenotypic test of pathogen inoculation demonstrated that MYB30 partially rescued the disease symptoms of sad2-5 caused by Pst DC3000, and that MYB30 worked downstream of SAD2 in plant pathogen defense. These results suggested that SAD2 might be involved in plant pathogen defense by mediating MYB30 nuclear trafficking. Taken together, our results revealed the important function of SAD2 in plant pathogen defense and enriched understanding of the mechanism of nucleocytoplasmic transport-mediated plant pathogen defense.

BACKGROUND: Different neural subtypes are selectively lost in diverse neurodegenerative diseases. Huntington\'s disease (HD) is an inherited neurodegenerative disease characterized by motor abnormalities that primarily affect the striatum. The Huntingtin (HTT) mutation involves an expanded CAG repeat, leading to insoluble polyQ, which renders GABA+ medium spiny neurons (MSN) more venerable to cell death. Human pluripotent stem cells (hPSCs) technology allows for the construction of disease-specific models, providing valuable cellular models for studying pathogenesis, drug screening, and high-throughput analysis.
METHODS: In this study, we established a method that allows for rapid and efficient generation of MSNs (> 90%) within 21 days from hPSC-derived neural progenitor cells, by introducing a specific combination of transcription factors.
RESULTS: We efficiently induced several neural subtypes, in parallel, based on the same cell source, and revealed that, compared to other neural subtypes, MSNs exhibited higher polyQ aggregation propensity and overexpression toxicity, more severe dysfunction in BDNF/TrkB signaling, greater susceptibility to BDNF withdrawal, and more severe disturbances in nucleocytoplasmic transport (NCT). We further found that the nuclear lamina protein LMNB1 was greatly reduced in HD neurons and mislocalized to the cytoplasm and axons. Knockdown of HTT or treatment with KPT335, an orally selective inhibitor of nuclear export (SINE), effectively attenuated the pathological phenotypes and alleviated neuronal death caused by BDNF withdrawal.
CONCLUSIONS: This study thus establishes an effective method for obtaining MSNs and underscores the necessity of using high-purity MSNs to study HD pathogenesis, especially the MSN-selective vulnerability.

Viruses have evolved intricate mechanisms to evade host antiviral responses and exploit cellular resources by manipulating the expression profile of host genes. During infection, viruses encode proteins with shutoff activity to globally inhibit host protein synthesis, which is an effective strategy for immune evasion. In this study, compelling evidence shows that infectious bursal disease virus (IBDV) infection triggers the suppression of host protein synthesis. Furthermore, using both in vitro and in vivo viral infection models, we have identified that IBDV specifically impedes the transcription of host genes via the shutoff activity of viral VP5, simultaneously conferring advantages to IBDV infection in these circumstances. The proposed mechanism suggests that VP5 competitively binds to RanBP1, disrupting the RanGDP/GTP gradient. This disruption interferes with cellular nucleocytoplasmic transport, impairing the nuclear import of proteins bearing nuclear localization signals. The nuclear transport of pivotal transcriptional regulatory factors, such as p65 and IFN regulatory factor 7, is also compromised, leading to the inhibition of pro-inflammatory cytokines and interferon expression. This newly discovered strategy employed by IBDV enables them to manipulate host gene expression, providing novel insights into how viruses evade host immune responses and establish infections.IMPORTANCEViruses manipulate host processes at various levels to regulate or evade both innate and adaptive immune responses, promoting self-survival and efficient transmission. The \"host shutoff,\" a global suppression of host gene expression mediated by various viruses, is considered a critical mechanism for evading immunity. In this study, we have validated the presence of host shutoff during infectious bursal disease virus (IBDV) infection and additionally uncovered that the viral protein VP5 plays a pivotal role in inhibiting the overall synthesis of host proteins, including cytokines, through a transcription-dependent pathway. VP5 competitively binds with RanBP1, leading to disruption of the Ran protein cycle and consequently interfering with nucleocytoplasmic transport, which ultimately results in the suppression of host gene transcription. These findings unveil a novel strategy employed by IBDV to evade host innate immunity and rapidly establish infection. This study also suggests a novel supplement to understanding the pathway through which viruses inhibit host protein synthesis.

Expansion of the GGGGCC-RNA repeat is a known cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), which currently have no cure. Recent studies have indicated the activation of Sigma-1 receptor plays an important role in providing neuroprotection, especially in ALS and Alzheimer\'s disease. Nevertheless, the mechanisms underlying Sigma-1R activation and its effect on (G4C2)n-RNA-induced cell death remain unclear. In this study, we demonstrated that fluvoxamine is a Sigma-1R agonist that can increase chaperone activity and stabilize the protein expression of Pom121 in (G4C2)31-RNA-expressing NSC34 cells, leading to increased colocalization at the nuclear envelope. Interestingly, fluvoxamine treatment increased Pom121 protein expression without affecting transcription. In C9orf72-ALS, the nuclear translocation of TFEB autophagy factor decreased owing to nucleocytoplasmic transport defects. Our results showed that pretreatment of NSC34 cells with fluvoxamine promoted the shuttling of TFEB into the nucleus and elevated the expression of LC3-II compared to the overexpression of (G4C2)31-RNA alone. Additionally, even when used alone, fluvoxamine increases Pom121 expression and TFEB translocation. To summarize, fluvoxamine may act as a promising repurposed medicine for patients with C9orf72-ALS, as it stabilizes the nucleoporin Pom121 and promotes the translocation of TFEB in (G4C2)31-RNA-expressing NSC34 cells.

CONCLUSIONS: Physiological and molecular tests show that NUP96 plays an important role in the plant response to salt stress, resulting from the reprogramming of transcriptomic profiles, which are likely to be mediated by the influence on the nuclear/cytosol shuttling of the key regulators of salt tolerance. As a key component of the nuclear pore complex (NPC), nucleoporin 96 (NUP96) is critical for modulating plant development and interactions with environmental factors, but whether NUP96 is involved in the salt response is still unknown. Here, we analyzed the role of Arabidopsis NUP96 under salt stress. The loss-of-function mutant nup96 exhibited salt sensitivity in terms of rosette growth and root elongation, and showed attenuated capacity in maintaining ion and ROS homeostasis, which could be compensated for by the overexpression of NUP96. RNA sequencing revealed that many salt-responsive genes were misregulated after NUP96 mutation, and especially NUP96 is required for the expression of a large portion of salt-induced genes. This is likely correlated with the activity in facilitating nuclear/cytosol transport of the underlying regulators in salt tolerance such as the transcription factor ATAP2, targeted by eight downregulated genes in nup96 under salt stress. Our results illustrate that NUP96 plays an important role in the salt response, probably by regulating the nucleocytoplasmic shuttling of key mRNAs or proteins associated with plant salt responsiveness.

Dysregulation of nucleocytoplasmic shuttling impairs cellular homeostasis and promotes cancer development. KPNB1 is a member of karyopherin β family, mediating the transportation of proteins from the cytoplasm to the nucleus. In a variety of cancers, the expression of KPNB1 is upregulated to facilitate tumor growth and progression. Both downregulation of KPNB1 level and inhibition of KPNB1 activity prevent the entry of cancer-related transcription factors into the nucleus, subsequently suppressing the proliferation and metastasis of cancer cells. Currently, five KPNB1 inhibitors have been reported and exhibited good efficacy against cancer. This paper provides an overview of the role and mechanism of KPNB1 in different cancers and KPNB1-targeted anticancer compounds which hold promise for the future.

Sentrin/small ubiquitin-like modifier (SUMO) has emerged as a powerful mediator regulating biological processes and participating in pathophysiological processes that cause human diseases, such as cancer, myocardial fibrosis and neurological disorders. Sumoylation has been shown to play a positive regulatory role in keloids. However, the sumoylation mechanism in keloids remains understudied. We proposed that sumoylation regulates keloids via a complex. RanGAP1 acted as a synergistic, functional partner of SUMOs in keloids. Nuclear accumulation of Smad4, a TGF-β/Smad pathway member, was associated with RanGAP1 after SUMO1 inhibition. RanGAP1*SUMO1 mediated the nuclear accumulation of Smad4 due to its impact on nuclear export and reduction in the dissociation of Smad4 and CRM1. We clarified a novel mechanism of positive regulation of sumoylation in keloids and demonstrated the function of sumoylation in Smad4 nuclear export. The NPC-associated RanGAP1*SUMO1 complex functions as a disassembly machine for the export receptor CRM1 and Smad4. Our research provides new perspectives for the mechanisms of keloids and nucleocytoplasmic transport.

CONCLUSIONS: Arabidopsis nucleoporin involved in the regulation of ethylene signaling via controlling of nucleocytoplasmic transport of mRNAs. The two-way transport of mRNAs between the nucleus and cytoplasm are controlled by the nuclear pore complex (NPC). In higher plants, the NPC contains at least 30 nucleoporins. The Arabidopsis nucleoporins are involved in various biological processes such as pathogen interaction, nodulation, cold response, flowering, and hormone signaling. However, little is known about the regulatory functions of the nucleoporin NUP160 and NUP96 in ethylene signaling pathway. In the present study, we provided data showing that the Arabidopsis nucleoporin NUP160 and NUP96 participate in ethylene signaling-related mRNAs nucleocytoplasmic transport. The Arabidopsis nucleoporin mutants (nup160, nup96-1, nup96-2) exhibited enhanced ethylene sensitivity. Nuclear qRT-PCR analysis and poly(A)-mRNA in situ hybridization showed that the nucleoporin mutants affected the nucleocytoplasmic transport of all the examined mRNAs, including the ethylene signaling-related mRNAs such as ETR2, ERS1, ERS2, EIN4, CTR1, EIN2, and EIN3. Transcriptome analysis of the nucleoporin mutants provided clues suggesting that the nucleoporin NUP160 and NUP96 may participate in ethylene signaling via various molecular mechanisms. These observations significantly advance our understanding of the regulatory mechanisms of nucleoporin proteins in ethylene signaling and ethylene response.

Cytoplasmic mislocalization and aggregation of TAR DNA-binding protein-43 (TDP-43) is a hallmark of the amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD) disease spectrum, causing both nuclear loss-of-function and cytoplasmic toxic gain-of-function phenotypes. While TDP-43 proteinopathy has been associated with defects in nucleocytoplasmic transport, this process is still poorly understood. Here we study the role of karyopherin-β1 (KPNB1) and other nuclear import receptors in regulating TDP-43 pathology.
We used immunostaining, immunoprecipitation, biochemical and toxicity assays in cell lines, primary neuron and organotypic mouse brain slice cultures, to determine the impact of KPNB1 on the solubility, localization, and toxicity of pathological TDP-43 constructs. Postmortem patient brain and spinal cord tissue was stained to assess KPNB1 colocalization with TDP-43 inclusions. Turbidity assays were employed to study the dissolution and prevention of aggregation of recombinant TDP-43 fibrils in vitro. Fly models of TDP-43 proteinopathy were used to determine the effect of KPNB1 on their neurodegenerative phenotype in vivo.
We discovered that several members of the nuclear import receptor protein family can reduce the formation of pathological TDP-43 aggregates. Using KPNB1 as a model, we found that its activity depends on the prion-like C-terminal region of TDP-43, which mediates the co-aggregation with phenylalanine and glycine-rich nucleoporins (FG-Nups) such as Nup62. KPNB1 is recruited into these co-aggregates where it acts as a molecular chaperone that reverses aberrant phase transition of Nup62 and TDP-43. These findings are supported by the discovery that Nup62 and KPNB1 are also sequestered into pathological TDP-43 aggregates in ALS/FTD postmortem CNS tissue, and by the identification of the fly ortholog of KPNB1 as a strong protective modifier in Drosophila models of TDP-43 proteinopathy. Our results show that KPNB1 can rescue all hallmarks of TDP-43 pathology, by restoring its solubility and nuclear localization, and reducing neurodegeneration in cellular and animal models of ALS/FTD.
Our findings suggest a novel NLS-independent mechanism where, analogous to its canonical role in dissolving the diffusion barrier formed by FG-Nups in the nuclear pore, KPNB1 is recruited into TDP-43/FG-Nup co-aggregates present in TDP-43 proteinopathies and therapeutically reverses their deleterious phase transition and mislocalization, mitigating neurodegeneration.