bims-nucpor Biomed News
on Nuclear pore complex and nucleoporins in stress, aging and disease
Issue of 2023–10–29
seven papers selected by
Sara Mingu, Johannes Gutenberg University
  1. Unveiling the complexity: assessing models describing the structure and function of the nuclear pore complex.
  2. Nuclear Import and Export of YAP and TAZ.
  3. From the sideline: tissue-specific nucleoporin function in health and disease, an update.
  4. Biomedical implications of nuclear transport.
  5. The nuclear pore Y-complex functions as a platform for transcriptional regulation of FLOWERING LOCUS C in Arabidopsis.
  6. Label-free imaging of nuclear membrane for analysis of nuclear import of viral complexes.
  7. A Structural Model for the Core Nup358-BicD2 Interface.
  1. Front Cell Dev Biol. 2023 ;11 1245939
    Unveiling the complexity: assessing models describing the structure and function of the nuclear pore complex.
    Coby Rush, Zecheng Jiang, Mark Tingey, Fiona Feng, Weidong Yang.
      The nuclear pore complex (NPC) serves as a pivotal subcellular structure, acting as a gateway that orchestrates nucleocytoplasmic transport through a selectively permeable barrier. Nucleoporins (Nups), particularly those containing phenylalanine-glycine (FG) motifs, play indispensable roles within this barrier. Recent advancements in technology have significantly deepened our understanding of the NPC's architecture and operational intricacies, owing to comprehensive investigations. Nevertheless, the conspicuous presence of intrinsically disordered regions within FG-Nups continues to present a formidable challenge to conventional static characterization techniques. Historically, a multitude of strategies have been employed to unravel the intricate organization and behavior of FG-Nups within the NPC. These endeavors have given rise to multiple models that strive to elucidate the structural layout and functional significance of FG-Nups. Within this exhaustive review, we present a comprehensive overview of these prominent models, underscoring their proposed dynamic and structural attributes, supported by pertinent research. Through a comparative analysis, we endeavor to shed light on the distinct characteristics and contributions inherent in each model. Simultaneously, it remains crucial to acknowledge the scarcity of unequivocal validation for any of these models, as substantiated by empirical evidence.
    Keywords:  intrinsically disordered protein; nuclear pore complex; nucleocytoplasmic transport; super-resolution light microscopy; transmembrane proteins
    DOI:  https://doi.org/10.3389/fcell.2023.1245939
  2. Cancers (Basel). 2023 Oct 12. pii: 4956. [Epub ahead of print]15(20):
    Nuclear Import and Export of YAP and TAZ.
    Michael Kofler, András Kapus.
      Yes-associated Protein (YAP) and its paralog Transcriptional Coactivator with PDZ-binding Motif (TAZ) are major regulators of gene transcription/expression, primarily controlled by the Hippo pathway and the cytoskeleton. Integrating an array of chemical and mechanical signals, they impact growth, differentiation, and regeneration. Accordingly, they also play key roles in tumorigenesis and metastasis formation. Their activity is primarily regulated by their localization, that is, Hippo pathway- and/or cytoskeleton-controlled cytosolic or nuclear sequestration. While many details of such prevailing retention models have been elucidated, much less is known about their actual nuclear traffic: import and export. Although their size is not far from the cutoff for passive diffusion through the nuclear pore complex (NPC), and they do not contain any classic nuclear localization (NLS) or nuclear export signal (NES), evidence has been accumulating that their shuttling involves mediated and thus regulatable/targetable processes. The aim of this review is to summarize emerging information/concepts about their nucleocytoplasmic shuttling, encompassing the relevant structural requirements (NLS, NES), nuclear transport receptors (NTRs, karyophererins), and NPC components, along with the potential transport mechanisms and their regulation. While dissecting retention vs. transport is often challenging, the emerging picture suggests that YAP/TAZ shuttles across the NPC via multiple, non-exclusive, mediated mechanisms, constituting a novel and intriguing facet of YAP/TAZ biology.
    Keywords:  YAP/TAZ/Yorkie; importins and exportins; mediated nuclear import; nuclear export; nuclear import signal and nuclear export sequence; nuclear pore complex
    DOI:  https://doi.org/10.3390/cancers15204956
  3. FEBS Lett. 2023 Oct 24.
    From the sideline: tissue-specific nucleoporin function in health and disease, an update.
    Ramona Jühlen, Birthe Fahrenkrog.
      The subcellular compartmentalisation of eukaryotic cells requires selective exchange between the cytoplasm and the nucleus. Intact nucleocytoplasmic transport is vital for normal cell function and mutations in the executing machinery have been causally linked to human disease. Central players in nucleocytoplasmic exchange are nuclear pore complexes (NPCs), which are built from ~30 distinct proteins collectively termed nucleoporins. Aberrant nucleoporin expression was detected in human cancers and autoimmune diseases since quite some time, while it was through the increasing use of next generation sequencing that mutations in nucleoporin genes associated with mainly rare hereditary diseases were revealed. The number of newly identified mutations is steadily increasing, as is the number of diseases. Mutational hotspots have emerged: mutations in the scaffold nucleoporins seemingly affect primarily inner organs, such as heart, kidney, and ovaries, whereas genetic alterations in peripheral, cytoplasmic nucleoporins affect primarily the central nervous system and development. In this review, we summarise latest insights on altered nucleoporin function in the context of human hereditary disorders, with a focus on those where mechanistic insights are beginning to emerge.
    Keywords:  NUP93; ciliopathies; hereditary disorder; nuclear pore complex; nucleoporin
    DOI:  https://doi.org/10.1002/1873-3468.14761
  4. FEBS Lett. 2023 Oct;597(20): 2499-2500
    Biomedical implications of nuclear transport.
    Nathalie J Arhel, Mark C Field.
      
    DOI:  https://doi.org/10.1002/1873-3468.14752
  5. Plant Cell. 2023 Oct 25. pii: koad271. [Epub ahead of print]
    The nuclear pore Y-complex functions as a platform for transcriptional regulation of FLOWERING LOCUS C in Arabidopsis.
    Penghui Huang, Xiaomei Zhang, Zhiyuan Cheng, Xu Wang, Yuchen Miao, Guowen Huang, Yong-Fu Fu, Xianzhong Feng.
      The nuclear pore complex (NPC) has multiple functions beyond the nucleo-cytoplasmic transport of large molecules. Sub-nuclear 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.
    DOI:  https://doi.org/10.1093/plcell/koad271
  6. J Virol Methods. 2023 Oct 22. pii: S0166-0934(23)00159-3. [Epub ahead of print]322 114834
    Label-free imaging of nuclear membrane for analysis of nuclear import of viral complexes.
    Andrew Ten Eyck, Yen-Cheng Chen, Levi Gifford, Dariana Torres-Rivera, Eva L Dyer, Gregory B Melikyan.
      HIV-1 enters the nucleus of non-dividing cells through the nuclear pore complex where it integrates into the host genome. The mechanism of HIV-1 nuclear import remains poorly understood. A powerful means to investigate the docking of HIV-1 at the nuclear pore and nuclear import of viral complexes is through single virus tracking in live cells. This approach necessitates fluorescence labeling of HIV-1 particles and the nuclear envelope, which may be challenging, especially in the context of primary cells. Here, we leveraged a deep neural network model for label-free visualization of the nuclear envelope using transmitted light microscopy. A training image set of cells with fluorescently labeled nuclear Lamin B1 (ground truth), along with the corresponding transmitted light images, was acquired and used to train our model to predict the morphology of the nuclear envelope in fixed cells. This protocol yielded accurate predictions of the nuclear membrane and was used in conjunction with virus infection to examine the nuclear entry of fluorescently labeled HIV-1 complexes. Analyses of HIV-1 nuclear import as a function of virus input yielded identical numbers of fluorescent viral complexes per nucleus using the ground truth and predicted nuclear membrane images. We also demonstrate the utility of predicting the nuclear envelope based on transmitted light images for multicolor fluorescence microscopy of infected cells. Importantly, we show that our model can be adapted to predict the nuclear membrane of live cells imaged at 37 °C, making this approach compatible with single virus tracking. Collectively, these findings demonstrate the utility of deep learning approaches for label-free imaging of cellular structures during early stages of virus infection.
    Keywords:  Deep learning; Label-free cell imaging; Nuclear membrane; Virus nuclear entry
    DOI:  https://doi.org/10.1016/j.jviromet.2023.114834
  7. Biomolecules. 2023 Sep 26. pii: 1445. [Epub ahead of print]13(10):
    A Structural Model for the Core Nup358-BicD2 Interface.
    James M Gibson, Xiaoxin Zhao, M Yusuf Ali, Sozanne R Solmaz, Chunyu Wang.
      Dynein motors facilitate the majority of minus-end-directed transport events on microtubules. The dynein adaptor Bicaudal D2 (BicD2) recruits the dynein machinery to several cellular cargo for transport, including Nup358, which facilitates a nuclear positioning pathway that is essential for the differentiation of distinct brain progenitor cells. Previously, we showed that Nup358 forms a "cargo recognition α-helix" upon binding to BicD2; however, the specifics of the BicD2-Nup358 interface are still not well understood. Here, we used AlphaFold2, complemented by two additional docking programs (HADDOCK and ClusPro) as well as mutagenesis, to show that the Nup358 cargo-recognition α-helix binds to BicD2 between residues 747 and 774 in an anti-parallel manner, forming a helical bundle. We identified two intermolecular salt bridges that are important to stabilize the interface. In addition, we uncovered a secondary interface mediated by an intrinsically disordered region of Nup358 that is directly N-terminal to the cargo-recognition α-helix and binds to BicD2 between residues 774 and 800. This is the same BicD2 domain that binds to the competing cargo adapter Rab6, which is important for the transport of Golgi-derived and secretory vesicles. Our results establish a structural basis for cargo recognition and selection by the dynein adapter BicD2, which facilitates transport pathways that are important for brain development.
    Keywords:  AlphaFold2; Bicaudal D2; Nup358; dynein; intracellular transport; nuclear positioning
    DOI:  https://doi.org/10.3390/biom13101445
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