bims-nucpor Biomed News
on Nuclear pore complex and nucleoporins in stress, aging and disease
Issue of 2022–02–06
eight papers selected by
Sara Mingu, Johannes Gutenberg University
  1. Crowding-induced phase separation of nuclear transport receptors in FG nucleoporin assemblies.
  2. Teaching old dogmas new tricks: recent insights into the nuclear import of HIV-1.
  3. Misregulation of the Nucleoporins 98 and 96 lead to defects in protein synthesis that promote hallmarks of tumorigenesis.
  4. Molecular Mechanism of SARS-CoVs Orf6 Targeting the Rae1-Nup98 Complex to Compete With mRNA Nuclear Export.
  5. Targeting Nuclear Export Proteins in Multiple Myeloma Therapy.
  6. Pan-cancer analysis reveals the roles of XPO1 in predicting prognosis and tumorigenesis.
  7. Importin alpha 1 is required for the nucleus entry of Fowl Adenovirus serotype 4 Fiber-1 protein.
  8. Fusion proteins drive cancer through phase separation.
  1. Elife. 2022 Jan 31. pii: e72627. [Epub ahead of print]11
    Crowding-induced phase separation of nuclear transport receptors in FG nucleoporin assemblies.
    Luke K Davis, Ian J Ford, Bart W Hoogenboom.
      The rapid (< 1 ms) transport of biological material to and from the cell nucleus is regulated by the nuclear pore complex (NPC). At the core of the NPC is a permeability barrier consisting of intrinsically disordered Phe-Gly (FG) nucleoporins (FG Nups). Various types of nuclear transport receptors (NTRs) facilitate transport by partitioning in the FG Nup assembly, overcoming the barrier by their affinity to the FG Nups, and comprise a significant fraction of proteins in the NPC barrier. In previous work Zahn et al. (2016), we revealed a universal physical behaviour in the experimentally observed binding of two well-characterized NTRs, NTF2 and the larger Importin-β, to different planar assemblies of FG Nups, with the binding behaviour defined by negative cooperativity. This was further validated by a minimal physical model that treated the FG Nups as flexible homopolymers and the NTRs as uniformly cohesive spheres. Here, we build upon our original study by first parametrizing our model to experimental data, and next predicting the effects of crowding by different types of NTRs. We show how varying the amounts of one type of NTR modulates how the other NTR penetrates the FG Nup assembly. Notably, at similar and physiologically relevant NTR concentrations, our model predicts demixed phases of NTF2 and Imp-β within the FG Nup assembly. The functional implication of NTR phase separation is that NPCs may sustain separate transport pathways that are determined by inter-NTR competition.
    Keywords:  physics of living systems
    DOI:  https://doi.org/10.7554/eLife.72627
  2. Curr Opin Virol. 2022 Feb 01. pii: S1879-6257(22)00010-4. [Epub ahead of print]53 101203
    Teaching old dogmas new tricks: recent insights into the nuclear import of HIV-1.
    Adarsh Dharan, Edward M Campbell.
      A hallmark feature of lentiviruses, which separates them from other members of the retrovirus family, is their ability to infect non-dividing cells by traversing the nuclear pore complex. The viral determinant that mediates HIV-1 nuclear import is the viral capsid (CA) protein, which forms the conical core protecting the HIV-1 genome in a mature virion. Recently, a series of novel approaches developed to monitor post-fusion events in infection have challenged previous textbook models of the viral life cycle, which envisage reverse transcription and disassembly of the capsid core as events that complete in the cytoplasm. In this review, we summarize these recent findings and describe their implications on our understanding of the spatiotemporal staging of HIV-1 infection with a focus on the nuclear import and its implications in other aspects of the viral lifecycle.
    DOI:  https://doi.org/10.1016/j.coviro.2022.101203
  3. Dis Model Mech. 2022 Feb 02. pii: dmm.049234. [Epub ahead of print]
    Misregulation of the Nucleoporins 98 and 96 lead to defects in protein synthesis that promote hallmarks of tumorigenesis.
    Ajai J Pulianmackal, Kiriaki Kanakousaki, Kerry A Flegel, Olga G Grushko, Ella Gourley, Emily Rozich, Laura A Buttitta.
      The Nucleoporin 98KD (Nup98) is a promiscuous translocation partner in hematological malignancies. Most disease models of Nup98 translocations involve ectopic expression of the fusion protein under study, leaving the endogenous Nup98 loci unperturbed. Overlooked in these approaches is the loss of one copy of normal Nup98 in addition to the loss of Nup96 - a second Nucleoporin encoded within the same mRNA and reading frame as Nup98, in translocations. Nup98 and 96 are also mutated in a number of other cancers, suggesting their disruption is not limited to blood cancers. We found that reducing Nup98-96 function in Drosophila melanogaster (where the Nup98-96 shared mRNA and reading frame is conserved) de-regulates the cell cycle. We find evidence of over-proliferation in tissues with reduced Nup98-96, counteracted by elevated apoptosis and aberrant signaling associated with chronic wounding. Reducing Nup98-96 function leads to defects in protein synthesis that trigger JNK signaling and contributes to hallmarks of tumorigenesis when apoptosis is inhibited. We suggest partial loss of Nup98-96 function in translocations could de-regulate protein synthesis leading to signaling that cooperates with other mutations to promote tumorigenesis.
    Keywords:  Apoptosis; Compensatory proliferation; Drosophila wing; JNK signaling; Nuclear Pore Complex; Ribosome biogenesis
    DOI:  https://doi.org/10.1242/dmm.049234
  4. Front Mol Biosci. 2021 ;8 813248
    Molecular Mechanism of SARS-CoVs Orf6 Targeting the Rae1-Nup98 Complex to Compete With mRNA Nuclear Export.
    Tinghan Li, Yibo Wen, Hangtian Guo, Tingting Yang, Haitao Yang, Xiaoyun Ji.
      The accessory protein Orf6 is uniquely expressed in sarbecoviruses including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which is an ongoing pandemic. SARS-CoV-2 Orf6 antagonizes host interferon signaling by inhibition of mRNA nuclear export through its interactions with the ribonucleic acid export 1 (Rae1)-nucleoporin 98 (Nup98) complex. Here, we confirmed the direct tight binding of Orf6 to the Rae1-Nup98 complex, which competitively inhibits RNA binding. We determined the crystal structures of both SARS-CoV-2 and SARS-CoV-1 Orf6 C-termini in complex with the Rae1-Nup98 heterodimer. In each structure, SARS-CoV Orf6 occupies the same potential mRNA-binding groove of the Rae1-Nup98 complex, comparable to the previously reported structures of other viral proteins complexed with Rae1-Nup98, indicating that the Rae1-Nup98 complex is a common target for different viruses to impair the nuclear export pathway. Structural analysis and biochemical studies highlight the critical role of the highly conserved methionine (M58) of SARS-CoVs Orf6. Altogether our data unravel a mechanistic understanding of SARS-CoVs Orf6 targeting the mRNA-binding site of the Rae1-Nup98 complex to compete with the nuclear export of host mRNA, which further emphasizes that Orf6 is a critical virulence factor of SARS-CoVs.
    Keywords:  ORF6; Rae1-Nup98 complex; SARS-CoV-2; crystal structure; mRNA nuclear export
    DOI:  https://doi.org/10.3389/fmolb.2021.813248
  5. BioDrugs. 2022 Feb 03.
    Targeting Nuclear Export Proteins in Multiple Myeloma Therapy.
    Shambavi Richard, Sundar Jagannath.
      Nuclear export proteins such as exportin-1 (XPO1) transport tumor-suppressor proteins and other growth-regulatory proteins from the nucleus to the cytoplasm. Overexpression of XPO1 has been observed in several cancers and correlates with shorter event-free and overall survival in multiple myeloma. Selinexor was developed as an oral first-in-class selective inhibitor of nuclear export (SINE) that inhibits XPO1. Preclinical studies in tumor cell lines and mouse models have demonstrated the efficacy of selinexor both as a single agent and in various combinations with known active antimyeloma agents. Results from the pivotal phase II STORM trial led to the US FDA approval of selinexor with dexamethasone in penta-refractory myeloma. Because of the feasibility of combining selinexor with other active antimyeloma agents, the multiarm STOMP trial was initiated and is ongoing, with impressive response rates reported in some of the combination arms thus far. The registrational phase III BOSTON trial demonstrated the superiority of selinexor in combination with bortezomib and dexamethasone as compared with bortezomib and dexamethasone in patients with relapsed refractory multiple myeloma (RRMM) who have received one to three prior anti-MM regimens. The toxicity profile of selinexor is well established and predictable and may be significant unless managed aggressively and preemptively. The most common side effects are thrombocytopenia, anemia, neutropenia, fatigue, nausea, anorexia, and weight loss. Hyponatremia and cataracts seem to be class effects. Other SINE compounds are now being studied in efforts to discover agents that will potentially be better tolerated. Eltanexor is an investigational SINE compound that has shown a more positive toxicity profile in preclinical studies, with reduced central nervous system penetration and gastrointestinal side effects, and is now undergoing clinical investigation. These and other trials will further clarify the role of these innovative agents in the therapeutic advancement of RRMM.
    DOI:  https://doi.org/10.1007/s40259-021-00514-6
  6. Transl Cancer Res. 2021 Nov;10(11): 4664-4679
    Pan-cancer analysis reveals the roles of XPO1 in predicting prognosis and tumorigenesis.
    Lei Zhao, Baiwei Luo, Liang Wang, Wei Chen, Manyu Jiang, Nengwei Zhang.
       Background: Exportin 1 (XPO1), a nuclear export protein, participates in many biological processes, including mRNA transport, nucleocytoplasmic transport, nuclear protein export, regulation of mRNA stability, and drug response. XPO1 plays key roles in many cancer types and may serve as a potential biomarker. It is significant to systematically elucidate the roles of XPO1 in various cancer types in terms of function, molecular biology, immunology, and clinical relevance.
    Methods: Data from UCSC Xena, CCLE, and CBioPortal were analyzed for the investigation of the differential expression of XPO1 across multiple cancer types. Clinical data were acquired to analyze the influence of XPO1 on the clinical characteristics of patients, such as survival outcome and clinical stage. The roles of XPO1 in the onset and progression of multiple cancers were expounded in terms of genetic changes at the molecular level [including tumor mutational burden (TMB), microsatellite instability (MSI), copy number variation (CNV), methylation, and gene co-expression], biological pathway changes, and the immune microenvironment.
    Results: XPO1 was overexpressed in various tumor types, which may be related to CNV. Clinical data analysis revealed that XPO1 may serve as a risk factor in tumors, such as adrenocortical carcinoma, liver hepatocellular carcinoma, and low-grade glioma, thereby affecting patient prognosis. XPO1 in multiple tumor types was also substantially correlated with clinical stage, patient gender, and patient age. In certain tumors, the expression level of XPO1 exerted a greater influence on TMB and MSI. It was also found that XPO1 inhibited the activity of immune cells in the tumor immune microenvironment, such as CD8+ T cells, and affected biological pathways, such as the cell cycle and oxidative phosphorylation, and drove the expression of cancer driver genes, immune checkpoint genes, and highly mutated genes.
    Conclusions: XPO1 is a potential pan-cancer risk factor as it may jointly promote tumor onset and progression by inhibiting the immune response, influencing relevant biological pathways, and promoting mutations in other genes.
    Keywords:  Exportin 1 (XPO1); immune microenvironment; microsatellite instability (MSI); pan-cancer; tumor mutational burden (TMB)
    DOI:  https://doi.org/10.21037/tcr-21-1646
  7. Vet Microbiol. 2022 Jan 31. pii: S0378-1135(22)00021-9. [Epub ahead of print]266 109351
    Importin alpha 1 is required for the nucleus entry of Fowl Adenovirus serotype 4 Fiber-1 protein.
    Ruiling Huang, Qing He, Shaohua Lu, Menghan Yan, Lihui Xu, Quanxi Wang.
      Fiber-1 protein (F1) is the structural protein of Fowl Adenovirus serotype 4 (FAdV-4), which could recondite the receptors of host cytomembrane. In this study, we firstly determined that F1 protein located in nucleus of LMH cells after infection with FAdV-4. We additionally revealed that F1 protein had a classic NLS, and the NLS was required for F1 nucleus entry, which was intently associated to the 26th Pro in NLS. The time rule result indicated that some F1 proteins firstly positioned in the nucleus 6 h posttranfection, and it entirely located in the nucleus 12 h posttranfection, then it ordinarily placed in cytoplasm 18 h posttranfection by means of microscopic fluorescence observation and Western Blotting. Then after transfection with pCI-neo-flag-F1 or infection with FAdV-4, the importin alpha 1 was once investigated whether or not it was required for F1 protein nucleus entry through immunofluorescence and/or Co-IP, results demonstrated that the F1 protein and importin alpha 1 co-located in the nucleus 6 h and 12 h posttranfection. The tiers of F1 protein vicinity in nucleus have been additionally investigated after knockdown expression or overexpression of importin alpha 1, and the results further revealed that importin alpha 1 used to be required for F1 protein nucleus entry. Finally, the function of F1 protein nucleus entry was investigated by qPCR, RT-PCR and Western Blotting, and the results revealed that F1 protein nucleus location was conducive to the proliferation of FAdV-4. In summary, we firstly reveal that the F1 protein of FAdV-4 locates in nucleus infected with FAdV-4, and confirm that importin alpha 1 binds to the NLS of F1 protein to nucleus localization, which promotes the proliferation of FAdV-4.
    Keywords:  Co-immunoprecipitation; Co-location; Fiber-1 protein; Fowl Adenovirus serotype 4; Importin alpha 1; Nuclear localization signal
    DOI:  https://doi.org/10.1016/j.vetmic.2022.109351
  8. Nat Cancer. 2021 Dec;2(12): 1285
    Fusion proteins drive cancer through phase separation.
    Ioanna Pavlaki.
      
    DOI:  https://doi.org/10.1038/s43018-021-00295-5
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