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1.
BMC Cancer ; 24(1): 353, 2024 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-38504158

RESUMO

NUP155 is reported to be correlated with tumor development. However, the role of NUP155 in tumor physiology and the tumor immune microenvironment (TIME) has not been previously examined. This study comprehensively investigated the expression, immunological function, and prognostic significance of NUP155 in different cancer types. Bioinformatics analysis revealed that NUP155 was upregulated in 26 types of cancer. Additionally, NUP155 upregulation was strongly correlated with advanced pathological or clinical stages and poor prognosis in several cancers. Furthermore, NUP155 was significantly and positively correlated with DNA methylation, tumor mutational burden, microsatellite instability, and stemness score in most cancers. Additionally, NUP155 was also found to be involved in TIME and closely associated with tumor infiltrating immune cells and immunoregulation-related genes. Functional enrichment analysis revealed a strong correlation between NUP155 and immunomodulatory pathways, especially antigen processing and presentation. The role of NUP155 in breast cancer has not been examined. This study, for the first time, demonstrated that NUP155 was upregulated in breast invasive carcinoma (BRCA) cells and revealed its oncogenic role in BRCA using molecular biology experiments. Thus, our study highlights the potential value of NUP155 as a biomarker in the assessment of prognostic prediction, tumor microenvironment and immunotherapeutic response in pan-cancer.


Assuntos
Neoplasias da Mama , Carcinoma , Humanos , Feminino , Neoplasias da Mama/genética , Apoptose , Mama , Proliferação de Células/genética , Prognóstico , Microambiente Tumoral/genética , Complexo de Proteínas Formadoras de Poros Nucleares/genética
2.
Front Immunol ; 15: 1330738, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38449868

RESUMO

Nucleoporins (NUPs) are cellular effectors of human immunodeficiency virus-1 (HIV-1) replication that support nucleocytoplasmic trafficking of viral components. However, these also non-canonically function as positive effectors, promoting proviral DNA integration into the host genome and viral gene transcription, or as negative effectors by associating with HIV-1 restriction factors, such as MX2, inhibiting the replication of HIV-1. Here, we investigated the regulatory role of NUP98 on HIV-1 as we observed a lowering of its endogenous levels upon HIV-1 infection in CD4+ T cells. Using complementary experiments in NUP98 overexpression and knockdown backgrounds, we deciphered that NUP98 negatively affected HIV-1 long terminal repeat (LTR) promoter activity and lowered released virus levels. The negative effect on promoter activity was independent of HIV-1 Tat, suggesting that NUP98 prevents the basal viral gene expression. ChIP-qPCR showed NUP98 to be associated with HIV-1 LTR, with the negative regulatory element (NRE) of HIV-1 LTR playing a dominant role in NUP98-mediated lowering of viral gene transcription. Truncated mutants of NUP98 showed that the attenuation of HIV-1 LTR-driven transcription is primarily contributed by its N-terminal region. Interestingly, the virus generated from the producer cells transiently expressing NUP98 showed lower infectivity, while the virus generated from NUP98 knockdown CD4+ T cells showed higher infectivity as assayed in TZM-bl cells, corroborating the anti-HIV-1 properties of NUP98. Collectively, we show a new non-canonical function of a nucleoporin adding to the list of moonlighting host factors regulating viral infections. Downregulation of NUP98 in a host cell upon HIV-1 infection supports the concept of evolutionary conflicts between viruses and host antiviral factors.


Assuntos
HIV-1 , Complexo de Proteínas Formadoras de Poros Nucleares , Humanos , Complexo de Proteínas Formadoras de Poros Nucleares/genética , Poro Nuclear/genética , Repetição Terminal Longa de HIV/genética , Expressão Gênica
3.
Nucleus ; 15(1): 2314297, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38383349

RESUMO

The separation of genetic material from bulk cytoplasm has enabled the evolution of increasingly complex organisms, allowing for the development of sophisticated forms of life. However, this complexity has created new categories of dysfunction, including those related to the movement of material between cellular compartments. In eukaryotic cells, nucleocytoplasmic trafficking is a fundamental biological process, and cumulative disruptions to nuclear integrity and nucleocytoplasmic transport are detrimental to cell survival. This is particularly true in post-mitotic neurons, where nuclear pore injury and errors to nucleocytoplasmic trafficking are strongly associated with neurodegenerative disease. In this review, we summarize the current understanding of nuclear pore biology in physiological and pathological contexts and discuss potential therapeutic approaches for addressing nuclear pore injury and dysfunctional nucleocytoplasmic transport.


Assuntos
Doenças Neurodegenerativas , Poro Nuclear , Humanos , Poro Nuclear/metabolismo , Núcleo Celular/metabolismo , Doenças Neurodegenerativas/metabolismo , Transporte Ativo do Núcleo Celular/fisiologia , Complexo de Proteínas Formadoras de Poros Nucleares/metabolismo
5.
Proc Natl Acad Sci U S A ; 121(4): e2313737121, 2024 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-38241438

RESUMO

Nuclear import and uncoating of the viral capsid are critical steps in the HIV-1 life cycle that serve to transport and release genomic material into the nucleus. Viral core import involves translocating the HIV-1 capsid at the nuclear pore complex (NPC). Notably, the central channel of the NPC appears to often accommodate and allow passage of intact HIV-1 capsid, though mechanistic details of the process remain to be fully understood. Here, we investigate the molecular interactions that operate in concert between the HIV-1 capsid and the NPC that regulate capsid translocation through the central channel. To this end, we develop a "bottom-up" coarse-grained (CG) model of the human NPC from recently released cryo-electron tomography structure and then construct composite membrane-embedded CG NPC models. We find that successful translocation from the cytoplasmic side to the NPC central channel is contingent on the compatibility of the capsid morphology and channel dimension and the proper orientation of the capsid approach to the channel from the cytoplasmic side. The translocation dynamics is driven by maximizing the contacts between phenylalanine-glycine nucleoporins at the central channel and the capsid. For the docked intact capsids, structural analysis reveals correlated striated patterns of lattice disorder likely related to the intrinsic capsid elasticity. Uncondensed genomic material inside the docked capsid augments the overall lattice disorder of the capsid. Our results suggest that the intrinsic "elasticity" can also aid the capsid to adapt to the stress and remain structurally intact during translocation.


Assuntos
Capsídeo , HIV-1 , Humanos , Capsídeo/metabolismo , HIV-1/genética , Poro Nuclear/metabolismo , Proteínas do Capsídeo/genética , Transporte Ativo do Núcleo Celular , Complexo de Proteínas Formadoras de Poros Nucleares/metabolismo , Translocação Genética , Elasticidade
6.
Nature ; 626(8000): 843-851, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38267583

RESUMO

HIV-1 infection requires nuclear entry of the viral genome. Previous evidence suggests that this entry proceeds through nuclear pore complexes (NPCs), with the 120 × 60 nm capsid squeezing through an approximately 60-nm-wide central channel1 and crossing the permeability barrier of the NPC. This barrier can be described as an FG phase2 that is assembled from cohesively interacting phenylalanine-glycine (FG) repeats3 and is selectively permeable to cargo captured by nuclear transport receptors (NTRs). Here we show that HIV-1 capsid assemblies can target NPCs efficiently in an NTR-independent manner and bind directly to several types of FG repeats, including barrier-forming cohesive repeats. Like NTRs, the capsid readily partitions into an in vitro assembled cohesive FG phase that can serve as an NPC mimic and excludes much smaller inert probes such as mCherry. Indeed, entry of the capsid protein into such an FG phase is greatly enhanced by capsid assembly, which also allows the encapsulated clients to enter. Thus, our data indicate that the HIV-1 capsid behaves like an NTR, with its interior serving as a cargo container. Because capsid-coating with trans-acting NTRs would increase the diameter by 10 nm or more, we suggest that such a 'self-translocating' capsid undermines the size restrictions imposed by the NPC scaffold, thereby bypassing an otherwise effective barrier to viral infection.


Assuntos
Proteínas do Capsídeo , Capsídeo , Glicina , HIV-1 , Complexo de Proteínas Formadoras de Poros Nucleares , Poro Nuclear , Fenilalanina , Humanos , Transporte Ativo do Núcleo Celular , Capsídeo/química , Capsídeo/metabolismo , Glicina/metabolismo , HIV-1/química , HIV-1/genética , HIV-1/metabolismo , Poro Nuclear/química , Poro Nuclear/metabolismo , Poro Nuclear/virologia , Complexo de Proteínas Formadoras de Poros Nucleares/química , Complexo de Proteínas Formadoras de Poros Nucleares/metabolismo , Permeabilidade , Fenilalanina/metabolismo , Solubilidade , Internalização do Vírus , Proteínas do Capsídeo/química , Proteínas do Capsídeo/metabolismo
8.
Cell Death Dis ; 15(1): 7, 2024 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-38177114

RESUMO

Manipulation of the subcellular localization of transcription factors by preventing their shuttling via the nuclear pore complex (NPC) emerges as a novel therapeutic strategy against cancer. One transmembrane component of the NPC is POM121, encoded by a tandem gene locus POM121A/C on chromosome 7. Overexpression of POM121 is associated with metabolic diseases (e.g., diabetes) and unfavorable clinical outcome in patients with colorectal cancer (CRC). Peroxisome proliferator-activated receptor-gamma (PPARγ) is a transcription factor with anti-diabetic and anti-tumoral efficacy. It is inhibited by export from the nucleus to the cytosol via the RAS-RAF-MEK1/2-ERK1/2 signaling pathway, a major oncogenic driver of CRC. We therefore hypothesized that POM121 participates in the transport of PPARγ across the NPC to regulate its transcriptional activity on genes involved in metabolic and tumor control. We found that POM121A/C mRNA was enriched and POM121 protein co-expressed with PPARγ in tissues from CRC patients conferring poor prognosis. Its interactome was predicted to include proteins responsible for tumor metabolism and immunity, and in-silico modeling provided insights into potential 3D structures of POM121. A peptide region downstream of the nuclear localization sequence (NLS) of POM121 was identified as a cytoplasmic interactor of PPARγ. POM121 positivity correlated with the cytoplasmic localization of PPARγ in patients with KRAS mutant CRC. In contrast, POM121A/C silencing by CRISPR/Cas9 sgRNA or siRNA enforced nuclear accumulation of PPARγ and activated PPARγ target genes promoting lipid metabolism and cell cycle arrest resulting in reduced proliferation of human CRC cells. Our data suggest the POM121-PPARγ axis as a potential drugable target in CRC.


Assuntos
Neoplasias , Poro Nuclear , Humanos , Poro Nuclear/metabolismo , PPAR gama/genética , PPAR gama/metabolismo , RNA Guia de Sistemas CRISPR-Cas , Complexo de Proteínas Formadoras de Poros Nucleares/metabolismo , Fatores de Transcrição/metabolismo , Neoplasias/metabolismo , Glicoproteínas de Membrana/metabolismo
9.
Elife ; 122024 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-38189406

RESUMO

Cells must maintain a pool of processed and charged transfer RNAs (tRNA) to sustain translation capacity and efficiency. Numerous parallel pathways support the processing and directional movement of tRNA in and out of the nucleus to meet this cellular demand. Recently, several proteins known to control messenger RNA (mRNA) transport were implicated in tRNA export. The DEAD-box Protein 5, Dbp5, is one such example. In this study, genetic and molecular evidence demonstrates that Dbp5 functions parallel to the canonical tRNA export factor Los1. In vivo co-immunoprecipitation data further shows Dbp5 is recruited to tRNA independent of Los1, Msn5 (another tRNA export factor), or Mex67 (mRNA export adaptor), which contrasts with Dbp5 recruitment to mRNA that is abolished upon loss of Mex67 function. However, as with mRNA export, overexpression of Dbp5 dominant-negative mutants indicates a functional ATPase cycle and that binding of Dbp5 to Gle1 is required by Dbp5 to direct tRNA export. Biochemical characterization of the Dbp5 catalytic cycle demonstrates the direct interaction of Dbp5 with tRNA (or double-stranded RNA) does not activate Dbp5 ATPase activity, rather tRNA acts synergistically with Gle1 to fully activate Dbp5. These data suggest a model where Dbp5 directly binds tRNA to mediate export, which is spatially regulated via Dbp5 ATPase activation at nuclear pore complexes by Gle1.


Assuntos
Complexo de Proteínas Formadoras de Poros Nucleares , Proteínas de Saccharomyces cerevisiae , Saccharomyces cerevisiae , Adenosina Trifosfatases/genética , Catálise , Complexo de Proteínas Formadoras de Poros Nucleares/genética , RNA Mensageiro/genética , RNA de Transferência/genética , Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/genética
10.
Dev Cell ; 59(4): 482-495.e6, 2024 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-38272027

RESUMO

Mutations or dysregulation of nucleoporins (Nups) are strongly associated with neural developmental diseases, yet the underlying mechanisms remain poorly understood. Here, we show that depletion of Nup Seh1 in radial glial progenitors results in defective neural progenitor proliferation and differentiation that ultimately manifests in impaired neurogenesis and microcephaly. This loss of stem cell proliferation is not associated with defects in the nucleocytoplasmic transport. Rather, transcriptome analysis showed that ablation of Seh1 in neural stem cells derepresses the expression of p21, and knockdown of p21 partially restored self-renewal capacity. Mechanistically, Seh1 cooperates with the NuRD transcription repressor complex at the nuclear periphery to regulate p21 expression. Together, these findings identified that Nups regulate brain development by exerting a chromatin-associated role and affecting neural stem cell proliferation.


Assuntos
Neocórtex , Células-Tronco Neurais , Animais , Camundongos , Diferenciação Celular , Expressão Gênica , Neocórtex/metabolismo , Complexo de Proteínas Formadoras de Poros Nucleares/genética , Complexo de Proteínas Formadoras de Poros Nucleares/metabolismo
11.
Nature ; 626(8000): 836-842, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38267582

RESUMO

HIV can infect non-dividing cells because the viral capsid can overcome the selective barrier of the nuclear pore complex and deliver the genome directly into the nucleus1,2. Remarkably, the intact HIV capsid is more than 1,000 times larger than the size limit prescribed by the diffusion barrier of the nuclear pore3. This barrier in the central channel of the nuclear pore is composed of intrinsically disordered nucleoporin domains enriched in phenylalanine-glycine (FG) dipeptides. Through multivalent FG interactions, cellular karyopherins and their bound cargoes solubilize in this phase to drive nucleocytoplasmic transport4. By performing an in vitro dissection of the nuclear pore complex, we show that a pocket on the surface of the HIV capsid similarly interacts with FG motifs from multiple nucleoporins and that this interaction licences capsids to penetrate FG-nucleoporin condensates. This karyopherin mimicry model addresses a key conceptual challenge for the role of the HIV capsid in nuclear entry and offers an explanation as to how an exogenous entity much larger than any known cellular cargo may be able to non-destructively breach the nuclear envelope.


Assuntos
Proteínas do Capsídeo , Glicina , HIV , Carioferinas , Mimetismo Molecular , Complexo de Proteínas Formadoras de Poros Nucleares , Poro Nuclear , Fenilalanina , Humanos , Transporte Ativo do Núcleo Celular , Proteínas do Capsídeo/química , Proteínas do Capsídeo/metabolismo , Difusão , Dipeptídeos/química , Dipeptídeos/metabolismo , Glicina/metabolismo , HIV/química , HIV/metabolismo , Técnicas In Vitro , Proteínas Intrinsicamente Desordenadas/química , Proteínas Intrinsicamente Desordenadas/metabolismo , Carioferinas/metabolismo , Poro Nuclear/química , Poro Nuclear/metabolismo , Poro Nuclear/virologia , Complexo de Proteínas Formadoras de Poros Nucleares/química , Complexo de Proteínas Formadoras de Poros Nucleares/metabolismo , Permeabilidade , Fenilalanina/metabolismo , Solubilidade , Internalização do Vírus , Capsídeo/química , Capsídeo/metabolismo
12.
PLoS Pathog ; 20(1): e1011640, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38215165

RESUMO

Retroviral reverse transcription starts within the capsid and uncoating and reverse transcription are mutually dependent. There is still debate regarding the timing and cellular location of HIV's uncoating and reverse transcription and whether it occurs solely in the cytoplasm, nucleus or both. HIV can infect non-dividing cells because there is active transport of the preintegration complex (PIC) across the nuclear membrane, but Murine Leukemia Virus (MLV) is thought to depend on cell division for replication and whether MLV uncoating and reverse transcription is solely cytoplasmic has not been studied. Here, we used NIH3T3 and primary mouse dendritic cells to determine where the different stages of reverse transcription occur and whether cell division is needed for nuclear entry. Our data strongly suggest that in both NIH3T3 cells and dendritic cells (DCs), the initial step of reverse transcription occurs in the cytoplasm. However, we detected MLV RNA/DNA hybrid intermediates in the nucleus of dividing NIH3T3 cells and non-dividing DCs, suggesting that reverse transcription can continue after nuclear entry. We also confirmed that the MLV PIC requires cell division to enter the nucleus of NIH3T3 cells. In contrast, we show that MLV can infect non-dividing primary DCs, although integration of MLV DNA in DCs still required the viral p12 protein. Knockdown of several nuclear pore proteins dramatically reduced the appearance of integrated MLV DNA in DCs but not NIH3T3 cells. Additionally, MLV capsid associated with the nuclear pore proteins NUP358 and NUP62 during infection. These findings suggest that simple retroviruses, like the complex retrovirus HIV, gain nuclear entry by traversing the nuclear pore complex in non-mitotic cells.


Assuntos
Infecções por HIV , Complexo de Proteínas Formadoras de Poros Nucleares , Animais , Camundongos , Complexo de Proteínas Formadoras de Poros Nucleares/genética , Células NIH 3T3 , Vírus da Leucemia Murina/genética , Proteínas Virais , Proteínas do Capsídeo , Retroviridae , DNA , Células Dendríticas
13.
J Exp Bot ; 75(1): 60-72, 2024 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-37849222

RESUMO

Nucleoporin 50 (Nup50) is an evolutionarily conserved protein that is a constituent of the nuclear pore complex (NPC); however, its physiological role in plants is unclear. Arabidopsis has two Nup50 proteins, Nup50a and Nup50b, which are highly expressed in developing seeds. Green fluoresceent protein (GFP)-fused Nup50a and Nup50b are localized exclusively in the nucleopolasm, implying an additional function beyond the NPC in the nuclear envelope. To investigate the function of Nup50s, we employed the CRISPR/Cas9 [clustered regularly interspaced palindromic repeats (CRISPR)/CRISPR-associated protein 9] system to generate a nup50a nup50b double mutant, which exhibited premature translation termination of both Nup50 proteins. While the mutant showed no significant abnormal phenotype during vegetative growth, the nup50a nup50b seeds had an abnormal shape compared with the wild type. Comparative transcriptomics using immature seeds revealed that Nup50s regulate the expression of various genes, including cell wall-related genes. The nup50a nup50b seeds exhibited reduced seed longevity and salinity stress tolerance. Tetrazolium uptake and mucilage release assays implied that the nup50a nup50b seeds had greater water permeability than the wild type. Taken together, our results imply that Nup50s play a critical role in seed formation by regulating gene expression.


Assuntos
Proteínas de Arabidopsis , Arabidopsis , Complexo de Proteínas Formadoras de Poros Nucleares , Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Regulação da Expressão Gênica de Plantas , Longevidade , Complexo de Proteínas Formadoras de Poros Nucleares/genética , Complexo de Proteínas Formadoras de Poros Nucleares/metabolismo , Estresse Salino , Sementes
14.
Cancer Genet ; 280-281: 1-5, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38056049

RESUMO

BACKGROUND: Only rare cases of acute myeloid leukemia (AML) have been shown to harbor a t(8;11)(p11.2;p15.4). This translocation is believed to involve the fusion of NSD3 or FGFR1 with NUP98; however, apart from targeted mRNA quantitative PCR analysis, no molecular approaches have been utilized to define the chimeric fusions present in these rare cases. CASE PRESENTATION: Here we present the case of a 51-year-old female with AML with myelodysplastic-related morphologic changes, 13q deletion and t(8;11), where initial fluorescence in situ hybridization (FISH) assays were consistent with the presence of NUP98 and FGFR1 rearrangements, and suggestive of NUP98/FGFR1 fusion. Using a streamlined clinical whole-genome sequencing approach, we resolved the breakpoints of this translocation to intron 4 of NSD3 and intron 12 of NUP98, indicating NUP98/NSD3 rearrangement as the likely underlying aberration. Furthermore, our approach identified small variants in WT1 and STAG2, as well as an interstitial deletion on the short arm of chromosome 12, which were cryptic in G-banded chromosomes. CONCLUSIONS: NUP98 fusions in acute leukemia are predictive of poor prognosis. The associated fusion partner and the presence of co-occurring mutations, such as WT1, further refine this prognosis with potential clinical implications. Using a clinical whole-genome sequencing analysis, we resolved t(8;11) breakpoints to NSD3 and NUP98, ruling out the involvement of FGFR1 suggested by FISH while also identifying multiple chromosomal and sequence level aberrations.


Assuntos
Leucemia Mieloide Aguda , Feminino , Humanos , Pessoa de Meia-Idade , Hibridização in Situ Fluorescente , Sequência de Bases , Leucemia Mieloide Aguda/genética , Complexo de Proteínas Formadoras de Poros Nucleares/genética , Translocação Genética
15.
Epilepsia Open ; 9(1): 424-431, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37943122

RESUMO

Focal cortical dysplasia (FCD) represents the most common cause of drug-resistant epilepsy in adult and pediatric surgical series. However, genetic factors contributing to severe phenotypes of FCD remain unknown. We present a patient with an exceptionally rapid development of drug-resistant epilepsy evolving in super-refractory status epilepticus. We performed multiple clinical (serial EEG, MRI), biochemical (metabolic and immunological screening), genetic (WES from blood- and brain-derived DNA), and histopathological investigations. The patient presented 1 month after an uncomplicated varicella infection. MRI was negative, as well as other biochemical and immunological examinations. Whole-exome sequencing of blood-derived DNA detected a heterozygous paternally inherited variant NM_006267.4(RANBP2):c.5233A>G p.(Ile1745Val) (Chr2[GRCh37]:g.109382228A>G), a gene associated with a susceptibility to infection-induced acute necrotizing encephalopathy. No combination of anti-seizure medication led to a sustained seizure freedom and the patient warranted induction of propofol anesthesia with high-dose intravenous midazolam and continuous respiratory support that however failed to abort seizure activity. Brain biopsy revealed FCD type IIa; this finding led to the indication of an emergency right-sided hemispherotomy that rendered the patient temporarily seizure-free. Postsurgically, he remains on antiseizure medication and experiences rare nondisabling seizures. This report highlights a uniquely severe clinical course of FCD putatively modified by the RANBP2 variant. PLAIN LANGUAGE SUMMARY: We report a case summary of a patient who came to our attention for epilepsy that could not be controlled with medication. His clinical course progressed rapidly to life-threatening status epilepticus with other unusual neurological findings. Therefore, we decided to surgically remove a piece of brain tissue in order to clarify the diagnosis that showed features of a structural brain abnormality associated with severe epilepsy, the focal cortical dysplasia. Later, a genetic variant in a gene associated with another condition, was found, and we hypothesize that this genetic variant could have contributed to this severe clinical course of our patient.


Assuntos
Encefalopatias , Epilepsia Resistente a Medicamentos , Epilepsia , Displasia Cortical Focal , Chaperonas Moleculares , Complexo de Proteínas Formadoras de Poros Nucleares , Estado Epiléptico , Criança , Pré-Escolar , Humanos , Masculino , Progressão da Doença , DNA , Epilepsia Resistente a Medicamentos/genética , Epilepsia Resistente a Medicamentos/cirurgia , Epilepsia/complicações , Midazolam , Estado Epiléptico/genética , Estado Epiléptico/cirurgia
17.
Plant Cell ; 36(2): 346-366, 2024 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-37877462

RESUMO

The nuclear pore complex (NPC) has multiple functions beyond the nucleo-cytoplasmic transport of large molecules. Subnuclear compartmentalization of chromatin is critical for gene expression in animals and yeast. However, the mechanism by which the NPC regulates gene expression is poorly understood in plants. Here we report that the Y-complex (Nup107-160 complex, a subcomplex of the NPC) self-maintains its nucleoporin homeostasis and modulates FLOWERING LOCUS C (FLC) transcription via changing histone modifications at this locus. We show that Y-complex nucleoporins are intimately associated with FLC chromatin through their interactions with histone H2A at the nuclear membrane. Fluorescence in situ hybridization assays revealed that Nup96, a Y-complex nucleoporin, enhances FLC positioning at the nuclear periphery. Nup96 interacted with HISTONE DEACETYLASE 6 (HDA6), a key repressor of FLC expression via histone modification, at the nuclear membrane to attenuate HDA6-catalyzed deposition at the FLC locus and change histone modifications. Moreover, we demonstrate that Y-complex nucleoporins interact with RNA polymerase II to increase its occupancy at the FLC locus, facilitating transcription. Collectively, our findings identify an attractive mechanism for the Y-complex in regulating FLC expression via tethering the locus at the nuclear periphery and altering its histone modification.


Assuntos
Proteínas de Arabidopsis , Arabidopsis , Arabidopsis/metabolismo , Histonas/genética , Histonas/metabolismo , Complexo de Proteínas Formadoras de Poros Nucleares/genética , Complexo de Proteínas Formadoras de Poros Nucleares/metabolismo , Poro Nuclear/genética , Poro Nuclear/metabolismo , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Hibridização in Situ Fluorescente , Proteínas de Domínio MADS/genética , Proteínas de Domínio MADS/metabolismo , Regulação da Expressão Gênica de Plantas/genética , Cromatina/genética , Cromatina/metabolismo , Flores/metabolismo , Histona Desacetilases/genética , Histona Desacetilases/metabolismo
18.
Pediatr Infect Dis J ; 43(3): e84-e86, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38091492

RESUMO

Acute necrotizing encephalopathy (ANE) is a rare childhood neurological disorder. The familiar type of ANE (ANE1) is associated with a mutation in the RANBP2 gene. Both SARS-CoV-2 and RANBP2 mutations are responsible for the manifestation of a hyper-inflammatory response that invades the central nervous system and plays a key role in the rapid progression of encephalopathy.


Assuntos
Encefalopatias , COVID-19 , Leucoencefalite Hemorrágica Aguda , Chaperonas Moleculares , Complexo de Proteínas Formadoras de Poros Nucleares , Humanos , Criança , Leucoencefalite Hemorrágica Aguda/diagnóstico , Leucoencefalite Hemorrágica Aguda/genética , SARS-CoV-2/genética , Mutação
19.
Hum Cell ; 37(1): 245-257, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37993750

RESUMO

Nucleoporin 93 (NUP93) is an important component of the nuclear pore complex, exhibiting pro-tumorigenic properties in some cancers. However, its function in esophageal squamous cell carcinoma (ESCC) has not been elucidated. This study aimed to investigate the effects of NUP93 in ESCC and the underlying mechanisms involved. Through analysis of public human cancer datasets, we observed higher expression of NUP93 in esophageal cancer tissues than in normal tissues. Stable ESCC cell lines with NUP93 overexpression or knockdown were established by lentiviral vector transduction and puromycin selection. NUP93 knockdown suppressed the proliferation, colony formation, cell cycle transition, migration, and invasion of ESCC cells, while the overexpression of NUP93 displayed opposite effects. NUP93 positively regulated epithelial-mesenchymal transition and AKT signaling transduction in ESCC cells. In addition, NUP93 increased the expression of programmed death ligand 1 (PD-L1) in ESCC cells and attenuated NK cell-mediated lysis of ESCC cells. In vivo experiments demonstrated that NUP93 promotes the growth of ESCC in nude mice, enhances Ki67 and PD-L1 expression, and promotes AKT signaling transduction in xenografts. Mechanistically, we demonstrated that the HECT domain E3 ubiquitin protein ligase 1 (HECTD1) contributes to the ubiquitination and degradation of NUP93 and acts as a tumor suppressor in ESCC. To conclude, this study has shown that NUP93 has pro-tumor properties in ESCC and that HECTD1 functions as an upstream regulator of NUP93 in ESCC. These findings may contribute to the investigation of potential therapeutic targets in ESCC.


Assuntos
Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Animais , Humanos , Camundongos , Antígeno B7-H1/metabolismo , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Transição Epitelial-Mesenquimal , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/genética , Carcinoma de Células Escamosas do Esôfago/patologia , Regulação Neoplásica da Expressão Gênica , Camundongos Nus , Complexo de Proteínas Formadoras de Poros Nucleares/genética , Complexo de Proteínas Formadoras de Poros Nucleares/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo
20.
Cell Rep ; 43(1): 113593, 2024 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-38113140

RESUMO

Nuclear mRNA export via nuclear pore complexes is an essential step in eukaryotic gene expression. Although factors involved in mRNA transport have been characterized, a comprehensive mechanistic understanding of this process and its regulation is lacking. Here, we use single-RNA imaging in yeast to show that cells use mRNA retention to control mRNA export during stress. We demonstrate that, upon glucose withdrawal, the essential RNA-binding factor Nab2 forms RNA-dependent condensate-like structures in the nucleus. This coincides with a reduced abundance of the DEAD-box ATPase Dbp5 at the nuclear pore. Depleting Dbp5, and consequently blocking mRNA export, is necessary and sufficient to trigger Nab2 condensation. The state of Nab2 condensation influences the extent of nuclear mRNA accumulation and can be recapitulated in vitro, where Nab2 forms RNA-dependent liquid droplets. We hypothesize that cells use condensation to regulate mRNA export and control gene expression during stress.


Assuntos
Complexo de Proteínas Formadoras de Poros Nucleares , Proteínas de Saccharomyces cerevisiae , Transporte Ativo do Núcleo Celular , Núcleo Celular/metabolismo , RNA Helicases DEAD-box/metabolismo , Complexo de Proteínas Formadoras de Poros Nucleares/metabolismo , Proteínas de Transporte Nucleocitoplasmático/genética , Proteínas de Transporte Nucleocitoplasmático/metabolismo , RNA/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo
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