Journal articles: 'RanBP2 (Nup358)'

1

Bernad, Rafael, Hella van der Velde, Maarten Fornerod, and Helen Pickersgill. "Nup358/RanBP2 Attaches to the Nuclear Pore Complex via Association with Nup88 and Nup214/CAN and Plays a Supporting Role in CRM1-Mediated Nuclear Protein Export." Molecular and Cellular Biology 24, no. 6 (March 15, 2004): 2373–84. http://dx.doi.org/10.1128/mcb.24.6.2373-2384.2004.

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ABSTRACT Nuclear pore complexes (NPCs) traverse the nuclear envelope (NE), providing a channel through which nucleocytoplasmic transport occurs. Nup358/RanBP2, Nup214/CAN, and Nup88 are components of the cytoplasmic face of the NPC. Here we show that Nup88 localizes midway between Nup358 and Nup214 and physically interacts with them. RNA interference of either Nup88 or Nup214 in human cells caused a strong reduction of Nup358 at the NE. Nup88 and Nup214 showed an interdependence at the NPC and were not affected by the absence of Nup358. These data indicate that Nup88 and Nup214 mediate the attachment of Nup358 to the NPC. We show that localization of the export receptor CRM1 at the cytoplasmic face of the NE is Nup358 dependent and represents its empty state. Also, removal of Nup358 causes a distinct reduction in nuclear export signal-dependent nuclear export. We propose that Nup358 provides both a platform for rapid disassembly of CRM1 export complexes and a binding site for empty CRM1 recycling into the nucleus.

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Shen, Qingtang, Yifan E. Wang, Mathew Truong, Kohila Mahadevan, Jingze J. Wu, Hui Zhang, Jiawei Li, Harrison W. Smith, Craig A. Smibert, and Alexander F. Palazzo. "RanBP2/Nup358 enhances miRNA activity by sumoylating Argonautes." PLOS Genetics 17, no. 2 (February 18, 2021): e1009378. http://dx.doi.org/10.1371/journal.pgen.1009378.

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Mutations in RanBP2 (also known as Nup358), one of the main components of the cytoplasmic filaments of the nuclear pore complex, contribute to the overproduction of acute necrotizing encephalopathy (ANE1)-associated cytokines. Here we report that RanBP2 represses the translation of the interleukin 6 (IL6) mRNA, which encodes a cytokine that is aberrantly up-regulated in ANE1. Our data indicates that soon after its production, the IL6 messenger ribonucleoprotein (mRNP) recruits Argonautes bound to let-7 microRNA. After this mRNP is exported to the cytosol, RanBP2 sumoylates mRNP-associated Argonautes, thereby stabilizing them and enforcing mRNA silencing. Collectively, these results support a model whereby RanBP2 promotes an mRNP remodelling event that is critical for the miRNA-mediated suppression of clinically relevant mRNAs, such as IL6.

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Swaminathan, Sowmya, Florian Kiendl, Roman Körner, Raffaella Lupetti, Ludger Hengst, and Frauke Melchior. "RanGAP1*SUMO1 is phosphorylated at the onset of mitosis and remains associated with RanBP2 upon NPC disassembly." Journal of Cell Biology 164, no. 7 (March 22, 2004): 965–71. http://dx.doi.org/10.1083/jcb.200309126.

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The RanGTPase activating protein RanGAP1 has essential functions in both nucleocytoplasmic transport and mitosis. In interphase, a significant fraction of vertebrate SUMO1-modified RanGAP1 forms a stable complex with the nucleoporin RanBP2/Nup358 at nuclear pore complexes. RanBP2 not only acts in the RanGTPase cycle but also is a SUMO1 E3 ligase. Here, we show that RanGAP1 is phosphorylated on residues T409, S428, and S442. Phosphorylation occurs before nuclear envelope breakdown and is maintained throughout mitosis. Nocodazole arrest leads to quantitative phosphorylation. The M-phase kinase cyclin B/Cdk1 phosphorylates RanGAP1 efficiently in vitro, and T409 phosphorylation correlates with nuclear accumulation of cyclin B1 in vivo. We find that phosphorylated RanGAP1 remains associated with RanBP2/Nup358 and the SUMO E2–conjugating enzyme Ubc9 in mitosis, hence mitotic phosphorylation may have functional consequences for the RanGTPase cycle and/or for RanBP2-dependent sumoylation.

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Hutten, Saskia, Annette Flotho, Frauke Melchior, and Ralph H. Kehlenbach. "The Nup358-RanGAP Complex Is Required for Efficient Importin α/β-dependent Nuclear Import." Molecular Biology of the Cell 19, no. 5 (May 2008): 2300–2310. http://dx.doi.org/10.1091/mbc.e07-12-1279.

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In vertebrate cells, the nucleoporin Nup358/RanBP2 is a major component of the filaments that emanate from the nuclear pore complex into the cytoplasm. Nup358 forms a complex with SUMOylated RanGAP1, the GTPase activating protein for Ran. RanGAP1 plays a pivotal role in the establishment of a RanGTP gradient across the nuclear envelope and, hence, in the majority of nucleocytoplasmic transport pathways. Here, we investigate the roles of the Nup358-RanGAP1 complex and of soluble RanGAP1 in nuclear protein transport, combining in vivo and in vitro approaches. Depletion of Nup358 by RNA interference led to a clear reduction of importin α/β-dependent nuclear import of various reporter proteins. In vitro, transport could be partially restored by the addition of importin β, RanBP1, and/or RanGAP1 to the transport reaction. In intact Nup358-depleted cells, overexpression of importin β strongly stimulated nuclear import, demonstrating that the transport receptor is the most rate-limiting factor at reduced Nup358-concentrations. As an alternative approach, we used antibody-inhibition experiments. Antibodies against RanGAP1 inhibited the enzymatic activity of soluble and nuclear pore–associated RanGAP1, as well as nuclear import and export. Although export could be fully restored by soluble RanGAP, import was only partially rescued. Together, these data suggest a dual function of the Nup358-RanGAP1 complex as a coordinator of importin β recycling and reformation of novel import complexes.

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Prunuske, Amy J., Jin Liu, Suzanne Elgort, Jomon Joseph, Mary Dasso, and Katharine S. Ullman. "Nuclear Envelope Breakdown Is Coordinated by Both Nup358/RanBP2 and Nup153, Two Nucleoporins with Zinc Finger Modules." Molecular Biology of the Cell 17, no. 2 (February 2006): 760–69. http://dx.doi.org/10.1091/mbc.e05-06-0485.

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When higher eukaryotic cells transition into mitosis, the nuclear envelope, nuclear pore complexes, and nuclear lamina are coordinately disassembled. The COPI coatomer complex, which plays a major role in membrane remodeling at the Golgi, has been implicated in the process of nuclear envelope breakdown and requires interactions at the nuclear pore complex for recruitment to this new site of action at mitosis. Nup153, a resident of the nuclear pore basket, was found to be involved in COPI recruitment, but the molecular nature of the interface between COPI and the nuclear pore has not been fully elucidated. To better understand what occurs at the nuclear pore at this juncture, we have probed the role of the nucleoporin Nup358/RanBP2. Nup358 contains a repetitive zinc finger domain with overall organization similar to a region within Nup153 that is critical to COPI association, yet inspection of these two zinc finger domains reveals features that also clearly distinguish them. Here, we found that the Nup358 zinc finger domain, but not a zinc finger domain from an unrelated protein, binds to COPI and dominantly inhibits progression of nuclear envelope breakdown in an assay that robustly recapitulates this process in vitro. Moreover, the Nup358 zinc finger domain interferes with COPI recruitment to the nuclear rim. Consistent with a role for this pore protein in coordinating nuclear envelope breakdown, Nup358-specific antibodies impair nuclear disassembly. Significantly, targeting either Nup153 or Nup358 for inhibition perturbs nuclear envelope breakdown, supporting a model in which these nucleoporins play nonredundant roles, perhaps contributing to COPI recruitment platforms on both the nuclear and cytoplasmic faces of the pore. We found that an individual zinc finger is the minimal interface for COPI association, although tandem zinc fingers are optimal. These results provide new information about the critical components of nuclear membrane remodeling and lay the foundation for a better understanding of how this process is regulated.

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Hutten, Saskia, and Ralph H. Kehlenbach. "Nup214 Is Required for CRM1-Dependent Nuclear Protein Export In Vivo." Molecular and Cellular Biology 26, no. 18 (September 15, 2006): 6772–85. http://dx.doi.org/10.1128/mcb.00342-06.

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ABSTRACT Nucleoporins mediate transport of macromolecules across the nuclear pore complex, yet the function of many individual nucleoporins is largely unresolved. To address this question, we depleted cells of the cytoplasmic nucleoporins Nup214/CAN and Nup358/RanBP2 by RNA interference. Depletion of Nup214 resulted in codepletion of its binding partner, Nup88. Nuclear pore complexes assembled in the absence of Nup214/Nup88 or Nup358 were fully functional in nuclear protein import, whereas nuclear mRNA export was slightly impaired. Depletion of Nup358 had only a minor effect on nuclear protein export. In contrast, depletion of Nup214/Nup88 led to strongly reduced CRM1-mediated export of the shuttling transcription factor NFAT as well as a human immunodeficiency virus-Rev derivative. A specific role of Nup214 in protein export is furthered by the biochemical properties of a high-affinity complex containing Nup214, CRM1, RanGTP, and an export cargo. Our results show that the Nup214/Nup88 complex is required for efficient CRM1-mediated transport, supporting a model involving a high-affinity binding site for CRM1 at Nup214 in the terminal steps of export.

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Jiang, Jing, Yifan E. Wang, Alexander F. Palazzo, and Qingtang Shen. "Roles of Nucleoporin RanBP2/Nup358 in Acute Necrotizing Encephalopathy Type 1 (ANE1) and Viral Infection." International Journal of Molecular Sciences 23, no. 7 (March 24, 2022): 3548. http://dx.doi.org/10.3390/ijms23073548.

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Ran Binding Protein 2 (RanBP2 or Nucleoporin358) is one of the main components of the cytoplasmic filaments of the nuclear pore complex. Mutations in the RANBP2 gene are associated with acute necrotizing encephalopathy type 1 (ANE1), a rare condition where patients experience a sharp rise in cytokine production in response to viral infection and undergo hyperinflammation, seizures, coma, and a high rate of mortality. Despite this, it remains unclear howRanBP2 and its ANE1-associated mutations contribute to pathology. Mounting evidence has shown that RanBP2 interacts with distinct viruses to regulate viral infection. In addition, RanBP2 may regulate innate immune response pathways. This review summarizes recent advances in our understanding of how mutations in RANBP2 contribute to ANE1 and discusses how RanBP2 interacts with distinct viruses and affects viral infection. Recent findings indicate that RanBP2 might be an important therapeutic target, not only in the suppression of ANE1-driven cytokine storms, but also to combat hyperinflammation in response to viral infections.

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Di Cesare, Erica, Sara Moroni, Jessica Bartoli, Michela Damizia, Maria Giubettini, Carolin Koerner, Veronica Krenn, Andrea Musacchio, and Patrizia Lavia. "Aurora B SUMOylation Is Restricted to Centromeres in Early Mitosis and Requires RANBP2." Cells 12, no. 3 (January 19, 2023): 372. http://dx.doi.org/10.3390/cells12030372.

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Conjugation with the small ubiquitin-like modifier (SUMO) modulates protein interactions and localisation. The kinase Aurora B, a key regulator of mitosis, was previously identified as a SUMOylation target in vitro and in assays with overexpressed components. However, where and when this modification genuinely occurs in human cells was not ascertained. Here, we have developed intramolecular Proximity Ligation Assays (PLA) to visualise SUMO-conjugated Aurora B in human cells in situ. We visualised Aurora B-SUMO products at centromeres in prometaphase and metaphase, which declined from anaphase onwards and became virtually undetectable at cytokinesis. In the mitotic window in which Aurora B/SUMO products are abundant, Aurora B co-localised and interacted with NUP358/RANBP2, a nucleoporin with SUMO ligase and SUMO-stabilising activity. Indeed, in addition to the requirement for the previously identified PIAS3 SUMO ligase, we found that NUP358/RANBP2 is also implicated in Aurora B-SUMO PLA product formation and centromere localisation. In summary, SUMOylation marks a distinctive window of Aurora B functions at centromeres in prometaphase and metaphase while being dispensable for functions exerted in cytokinesis, and RANBP2 contributes to this control, adding a novel layer to modulation of Aurora B functions during mitosis.

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Li, Jiawei, Lili Su, Jing Jiang, Yifan E. Wang, Yingying Ling, Yi Qiu, Huahui Yu, et al. "RanBP2/Nup358 Mediates Sumoylation of STAT1 and Antagonizes Interferon-α-Mediated Antiviral Innate Immunity." International Journal of Molecular Sciences 25, no. 1 (December 25, 2023): 299. http://dx.doi.org/10.3390/ijms25010299.

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Type I interferon (IFN-I)-induced signaling plays a critical role in host antiviral innate immune responses. Despite this, the mechanisms that regulate this signaling pathway have yet to be fully elucidated. The nucleoporin Ran Binding Protein 2 (RanBP2) (also known as Nucleoporin 358 KDa, Nup358) has been implicated in a number of cellular processes, including host innate immune signaling pathways, and is known to influence viral infection. In this study, we documented that RanBP2 mediates the sumoylation of signal transducers and activators of transcription 1 (STAT1) and inhibits IFN-α-induced signaling. Specifically, we found that RanBP2-mediated sumoylation inhibits the interaction of STAT1 and Janus kinase 1 (JAK1), as well as the phosphorylation and nuclear accumulation of STAT1 after IFN-α stimulation, thereby antagonizing the IFN-α-mediated antiviral innate immune signaling pathway and promoting viral infection. Our findings not only provide insights into a novel function of RanBP2 in antiviral innate immunity but may also contribute to the development of new antiviral therapeutic strategies.

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Palazzo, Alexander F., Jomon Joseph, Ming Lim, and Kiran T. Thakur. "Workshop on RanBP2/Nup358 and acute necrotizing encephalopathy." Nucleus 13, no. 1 (April 29, 2022): 154–69. http://dx.doi.org/10.1080/19491034.2022.2069071.

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11

Hamada, Masakazu, Anna Haeger, Karthik B. Jeganathan, Janine H. van Ree, Liviu Malureanu, Sarah Wälde, Jomon Joseph, Ralph H. Kehlenbach, and Jan M. van Deursen. "Ran-dependent docking of importin-β to RanBP2/Nup358 filaments is essential for protein import and cell viability." Journal of Cell Biology 194, no. 4 (August 22, 2011): 597–612. http://dx.doi.org/10.1083/jcb.201102018.

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RanBP2/Nup358, the major component of the cytoplasmic filaments of the nuclear pore complex (NPC), is essential for mouse embryogenesis and is implicated in both macromolecular transport and mitosis, but its specific molecular functions are unknown. Using RanBP2 conditional knockout mouse embryonic fibroblasts and a series of mutant constructs, we show that transport, rather than mitotic, functions of RanBP2 are required for cell viability. Cre-mediated RanBP2 inactivation caused cell death with defects in M9- and classical nuclear localization signal (cNLS)–mediated protein import, nuclear export signal–mediated protein export, and messenger ribonucleic acid export but no apparent mitotic failure. A short N-terminal RanBP2 fragment harboring the NPC-binding domain, three phenylalanine-glycine motifs, and one Ran-binding domain (RBD) corrected all transport defects and restored viability. Mutation of the RBD within this fragment caused lethality and perturbed binding to Ran guanosine triphosphate (GTP)–importin-β, accumulation of importin-β at nuclear pores, and cNLS-mediated protein import. These data suggest that a critical function of RanBP2 is to capture recycling RanGTP–importin-β complexes at cytoplasmic fibrils to allow for adequate cNLS-mediated cargo import.

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Walther, Tobias C., Helen S. Pickersgill, Volker C. Cordes, Martin W. Goldberg, Terry D. Allen, Iain W. Mattaj, and Maarten Fornerod. "The cytoplasmic filaments of the nuclear pore complex are dispensable for selective nuclear protein import." Journal of Cell Biology 158, no. 1 (July 8, 2002): 63–77. http://dx.doi.org/10.1083/jcb.200202088.

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The nuclear pore complex (NPC) mediates bidirectional macromolecular traffic between the nucleus and cytoplasm in eukaryotic cells. Eight filaments project from the NPC into the cytoplasm and are proposed to function in nuclear import. We investigated the localization and function of two nucleoporins on the cytoplasmic face of the NPC, CAN/Nup214 and RanBP2/Nup358. Consistent with previous data, RanBP2 was localized at the cytoplasmic filaments. In contrast, CAN was localized near the cytoplasmic coaxial ring. Unexpectedly, extensive blocking of RanBP2 with gold-conjugated antibodies failed to inhibit nuclear import. Therefore, RanBP2-deficient NPCs were generated by in vitro nuclear assembly in RanBP2-depleted Xenopus egg extracts. NPCs were formed that lacked cytoplasmic filaments, but that retained CAN. These nuclei efficiently imported nuclear localization sequence (NLS) or M9 substrates. NPCs lacking CAN retained RanBP2 and cytoplasmic filaments, and showed a minor NLS import defect. NPCs deficient in both CAN and RanBP2 displayed no cytoplasmic filaments and had a strikingly immature cytoplasmic appearance. However, they showed only a slight reduction in NLS-mediated import, no change in M9-mediated import, and were normal in growth and DNA replication. We conclude that RanBP2 is the major nucleoporin component of the cytoplasmic filaments of the NPC, and that these filaments do not have an essential role in importin α/β– or transportin-dependent import.

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Roscioli, Emanuele, Laura Di Francesco, Alessio Bolognesi, Maria Giubettini, Serena Orlando, Amnon Harel, Maria Eugenia Schininà, and Patrizia Lavia. "Importin-β negatively regulates multiple aspects of mitosis including RANGAP1 recruitment to kinetochores." Journal of Cell Biology 196, no. 4 (February 13, 2012): 435–50. http://dx.doi.org/10.1083/jcb.201109104.

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Importin-β is the main vector for interphase nuclear protein import and plays roles after nuclear envelope breakdown. Here we show that importin-β regulates multiple aspects of mitosis via distinct domains that interact with different classes of proteins in human cells. The C-terminal region (which binds importin-α) inhibits mitotic spindle pole formation. The central region (harboring nucleoporin-binding sites) regulates microtubule dynamic functions and interaction with kinetochores. Importin-β interacts through this region with NUP358/RANBP2, which in turn binds SUMO-conjugated RANGAP1 in nuclear pores. We show that this interaction continues after nuclear pore disassembly. Overexpression of importin-β, or of the nucleoporin-binding region, inhibited RANGAP1 recruitment to mitotic kinetochores, an event that is known to require microtubule attachment and the exportin CRM1. Co-expressing either importin-β–interacting RANBP2 fragments, or CRM1, restored RANGAP1 to kinetochores and rescued importin-β–dependent mitotic dynamic defects. These results reveal previously unrecognized importin-β functions at kinetochores exerted via RANBP2 and opposed by CRM1.

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Kassube, Susanne A., Tobias Stuwe, Daniel H. Lin, C. Danielle Antonuk, Johanna Napetschnig, Günter Blobel, and André Hoelz. "Crystal Structure of the N-Terminal Domain of Nup358/RanBP2." Journal of Molecular Biology 423, no. 5 (November 2012): 752–65. http://dx.doi.org/10.1016/j.jmb.2012.08.026.

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Stade, Katrin, Frank Vogel, Ingrid Schwienhorst, Birgit Meusser, Corinna Volkwein, Brigitte Nentwig, R. Jürgen Dohmen, and Thomas Sommer. "A Lack of SUMO Conjugation Affects cNLS-dependent Nuclear Protein Import in Yeast." Journal of Biological Chemistry 277, no. 51 (October 18, 2002): 49554–61. http://dx.doi.org/10.1074/jbc.m207991200.

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Yeast SUMO (Smt3) and its mammalian ortholog SUMO-1 are ubiquitin-like proteins that can reversibly be conjugated to other proteins. Among the substrates for SUMO modification in vertebrates are RanGAP1 and RanBP2/Nup358, two proteins previously implicated in nucleocytoplasmic transport. Sumoylated RanGAP1 binds to the nuclear pore complex via RanBP2/Nup358, a giant nucleoporin, which was recently reported to act as a SUMO E3 ligase on some nuclear substrates. However, no direct evidence for a role of the SUMO system in nuclear transport has been obtained so far. By the use of conditional yeast mutants, we examined nuclear protein importin vivo. We show here that cNLS-dependent protein import is impaired in mutants with defective Ulp1 and Uba2, two enzymes involved in the SUMO conjugation reaction. In contrast, other transport pathways such as rgNLS-mediated protein import and mRNA export are not affected. Furthermore, we find that the yeast importin-α subunit Srp1 accumulates in the nucleus ofulp1anduba2strains but not the importin-β subunit Kap95, indicating that a lack of Srp1 export might impair cNLS import. In summary, our results provide evidence that SUMO modification in yeast, as has been suspected for vertebrates, plays an important role in nucleocytoplasmic trafficking.

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Forler, Daniel, Gwénaël Rabut, Francesca D. Ciccarelli, Andrea Herold, Thomas Köcher, Ricarda Niggeweg, Peer Bork, Jan Ellenberg, and Elisa Izaurralde. "RanBP2/Nup358 Provides a Major Binding Site for NXF1-p15 Dimers at the Nuclear Pore Complex and Functions in Nuclear mRNA Export." Molecular and Cellular Biology 24, no. 3 (February 1, 2004): 1155–67. http://dx.doi.org/10.1128/mcb.24.3.1155-1167.2004.

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ABSTRACT Metazoan NXF1-p15 heterodimers promote the nuclear export of bulk mRNA across nuclear pore complexes (NPCs). In vitro, NXF1-p15 forms a stable complex with the nucleoporin RanBP2/Nup358, a component of the cytoplasmic filaments of the NPC, suggesting a role for this nucleoporin in mRNA export. We show that depletion of RanBP2 from Drosophila cells inhibits proliferation and mRNA export. Concomitantly, the localization of NXF1 at the NPC is strongly reduced and a significant fraction of this normally nuclear protein is detected in the cytoplasm. Under the same conditions, the steady-state subcellular localization of other nuclear or cytoplasmic proteins and CRM1-mediated protein export are not detectably affected, indicating that the release of NXF1 into the cytoplasm and the inhibition of mRNA export are not due to a general defect in NPC function. The specific role of RanBP2 in the recruitment of NXF1 to the NPC is highlighted by the observation that depletion of CAN/Nup214 also inhibits cell proliferation and mRNA export but does not affect NXF1 localization. Our results indicate that RanBP2 provides a major binding site for NXF1 at the cytoplasmic filaments of the NPC, thereby restricting its diffusion in the cytoplasm after NPC translocation. In RanBP2-depleted cells, NXF1 diffuses freely through the cytoplasm. Consequently, the nuclear levels of the protein decrease and export of bulk mRNA is impaired.

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Kuersten, Scott, Gert-Jan Arts, Tobias C. Walther, Ludwig Englmeier, and Iain W. Mattaj. "Steady-State Nuclear Localization of Exportin-t Involves RanGTP Binding and Two Distinct Nuclear Pore Complex Interaction Domains." Molecular and Cellular Biology 22, no. 16 (August 15, 2002): 5708–20. http://dx.doi.org/10.1128/mcb.22.16.5708-5720.2002.

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ABSTRACT Vertebrate tRNA export receptor exportin-t (Xpo-t) binds to RanGTP and mature tRNAs cooperatively to form a nuclear export complex. Xpo-t shuttles bidirectionally through nuclear pore complexes (NPCs) but is mainly nuclear at steady state. The steady-state distribution of Xpo-t is shown to depend on its interaction with RanGTP. Two distinct Xpo-t NPC interaction domains that bind differentially to peripherally localized nucleoporins in vitro are identified. The N terminus binds to both Nup153 and RanBP2/Nup358 in a RanGTP-dependent manner, while the C terminus binds to CAN/Nup214 independently of Ran. We propose that these interactions increase the concentration of tRNA export complexes and of empty Xpo-t in the vicinity of NPCs and thus increase the efficiency of the Xpo-t transport cycle.

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Sadasivan, Jibin, Marli Vlok, Xinying Wang, Arabinda Nayak, Raul Andino, and Eric Jan. "Targeting Nup358/RanBP2 by a viral protein disrupts stress granule formation." PLOS Pathogens 18, no. 12 (December 1, 2022): e1010598. http://dx.doi.org/10.1371/journal.ppat.1010598.

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Viruses have evolved mechanisms to modulate cellular pathways to facilitate infection. One such pathway is the formation of stress granules (SG), which are ribonucleoprotein complexes that assemble during translation inhibition following cellular stress. Inhibition of SG assembly has been observed under numerous virus infections across species, suggesting a conserved fundamental viral strategy. However, the significance of SG modulation during virus infection is not fully understood. The 1A protein encoded by the model dicistrovirus, Cricket paralysis virus (CrPV), is a multifunctional protein that can bind to and degrade Ago-2 in an E3 ubiquitin ligase-dependent manner to block the antiviral RNA interference pathway and inhibit SG formation. Moreover, the R146 residue of 1A is necessary for SG inhibition and CrPV infection in both Drosophila S2 cells and adult flies. Here, we uncoupled CrPV-1A’s functions and provide insight into its underlying mechanism for SG inhibition. CrPV-1A mediated inhibition of SGs requires the E3 ubiquitin-ligase binding domain and the R146 residue, but not the Ago-2 binding domain. Wild-type but not mutant CrPV-1A R146A localizes to the nuclear membrane which correlates with nuclear enrichment of poly(A)+ RNA. Transcriptome changes in CrPV-infected cells are dependent on the R146 residue. Finally, Nup358/RanBP2 is targeted and degraded in CrPV-infected cells in an R146-dependent manner and the depletion of Nup358 blocks SG formation. We propose that CrPV utilizes a multiprong strategy whereby the CrPV-1A protein interferes with a nuclear event that contributes to SG inhibition in order to promote infection.

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Saitoh, Hisato, Maryann Delli Pizzi, and Jian Wang. "Perturbation of SUMOlation Enzyme Ubc9 by Distinct Domain within Nucleoporin RanBP2/Nup358." Journal of Biological Chemistry 277, no. 7 (November 14, 2001): 4755–63. http://dx.doi.org/10.1074/jbc.m104453200.

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Lin, Daniel H., Stephan Zimmermann, Tobias Stuwe, Evelyn Stuwe, and André Hoelz. "Structural and Functional Analysis of the C-Terminal Domain of Nup358/RanBP2." Journal of Molecular Biology 425, no. 8 (April 2013): 1318–29. http://dx.doi.org/10.1016/j.jmb.2013.01.021.

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Saitoh, H., C. A. Cooke, W. H. Burgess, W. C. Earnshaw, and M. Dasso. "Direct and indirect association of the small GTPase ran with nuclear pore proteins and soluble transport factors: studies in Xenopus laevis egg extracts." Molecular Biology of the Cell 7, no. 9 (September 1996): 1319–34. http://dx.doi.org/10.1091/mbc.7.9.1319.

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Ran is a small GTPase that is required for protein import, mRNA export, and the maintenance of nuclear structures. To gain a better understanding of Ran's role in the nucleus, we have sought to use Xenopus egg extracts for the purification and characterization of proteins from egg extracts bound with a high affinity to a glutathione-S-transferase-Ran fusion protein (GST-Ran). We found that GST-Ran associates specifically with at least 10 extract proteins. We determined the identifies of six Ran-interacting proteins (Rips), and found that they include RanBP2/Nup358, Nup153, Importin beta, hsc70, RCC1, and RanBP1. On the basis of peptide sequence, a seventh Rip (p88) seems to be similar but not identical to Fug1/RanGAP1, the mammalian Ran-GTPase-activating protein. Gel filtration analysis of endogenous extract proteins suggests that Importin beta acts as a primary GTP-Ran effector. Both Ran and Importin beta are coimmunoprecipitated by anti-p340RanBP2 antibodies in the presence of nonhydrolyzable GTP analogues, suggesting that Ran-Importin beta complexes interact with p340RanBP2. Two other Rips, p18 and p88, are coprecipitated with p340RanBP2 in a nucleotide-independent manner. Analysis of the Ran-GTPase pathway in Xenopus extracts allows the examination of interactions between Ran-associated proteins under conditions that resemble in vivo conditions more closely than in assays with purified components, and it thereby allows additional insights into the molecular mechanism of nuclear transport.

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Hashizume, C., A. Kobayashi, and R. W. Wong. "Down-modulation of nucleoporin RanBP2/Nup358 impaired chromosomal alignment and induced mitotic catastrophe." Cell Death & Disease 4, no. 10 (October 2013): e854-e854. http://dx.doi.org/10.1038/cddis.2013.370.

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23

Mahadevan, Kohila, Hui Zhang, Abdalla Akef, Xianying A. Cui, Serge Gueroussov, Can Cenik, Frederick P. Roth, and Alexander F. Palazzo. "RanBP2/Nup358 Potentiates the Translation of a Subset of mRNAs Encoding Secretory Proteins." PLoS Biology 11, no. 4 (April 23, 2013): e1001545. http://dx.doi.org/10.1371/journal.pbio.1001545.

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24

Liu, Yi, Michael J. Trnka, Shenheng Guan, Doyoung Kwon, Do-Hyung Kim, J. J. Chen, Peter A. Greer, A. L. Burlingame, and Maria Almira Correia. "A Novel Mechanism for NF-κB-activation via IκB-aggregation: Implications for Hepatic Mallory-Denk-Body Induced Inflammation." Molecular & Cellular Proteomics 19, no. 12 (September 10, 2020): 1968–85. http://dx.doi.org/10.1074/mcp.ra120.002316.

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Mallory-Denk-bodies (MDBs) are hepatic protein aggregates associated with inflammation both clinically and in MDB-inducing models. Similar protein aggregation in neurodegenerative diseases also triggers inflammation and NF-κB activation. However, the precise mechanism that links protein aggregation to NF-κB-activation and inflammatory response remains unclear. Herein we find that treating primary hepatocytes with MDB-inducing agents (N-methylprotoporphyrin (NMPP), protoporphyrin IX (PPIX), or Zinc-protoporphyrin IX (ZnPP)) elicited an IκBα-loss with consequent NF-κB activation. Four known mechanisms of IκBα-loss i.e. the canonical ubiquitin-dependent proteasomal degradation (UPD), autophagic-lysosomal degradation, calpain degradation and translational inhibition, were all probed and excluded. Immunofluorescence analyses of ZnPP-treated cells coupled with 8 M urea/CHAPS-extraction revealed that this IκBα-loss was due to its sequestration along with IκBβ into insoluble aggregates, thereby releasing NF-κB. Through affinity pulldown, proximity biotinylation by antibody recognition, and other proteomic analyses, we verified that NF-κB subunit p65, which stably interacts with IκBα under normal conditions, no longer binds to it upon ZnPP-treatment. Additionally, we identified 10 proteins that interact with IκBα under baseline conditions, aggregate upon ZnPP-treatment, and maintain the interaction with IκBα after ZnPP-treatment, either by cosequestering into insoluble aggregates or through a different mechanism. Of these 10 proteins, the nucleoporins Nup153 and Nup358/RanBP2 were identified through RNA-interference, as mediators of IκBα-nuclear import. The concurrent aggregation of IκBα, NUP153, and RanBP2 upon ZnPP-treatment, synergistically precluded the nuclear entry of IκBα and its consequent binding and termination of NF-κB activation. This novel mechanism may account for the protein aggregate-induced inflammation observed in liver diseases, thus identifying novel targets for therapeutic intervention. Because of inherent commonalities this MDB cell model is a bona fide protoporphyric model, making these findings equally relevant to the liver inflammation associated with clinical protoporphyria.

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Wälde, Sarah, Ketan Thakar, Saskia Hutten, Christiane Spillner, Annegret Nath, Ulrich Rothbauer, Stefan Wiemann, and Ralph H. Kehlenbach. "The Nucleoporin Nup358/RanBP2 Promotes Nuclear Import in a Cargo- and Transport Receptor-Specific Manner." Traffic 13, no. 2 (November 21, 2011): 218–33. http://dx.doi.org/10.1111/j.1600-0854.2011.01302.x.

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Sharma, Manisha, Cara Jamieson, Michael Johnson, Mark P. Molloy, and Beric R. Henderson. "Specific Armadillo Repeat Sequences Facilitate β-Catenin Nuclear Transport in Live Cells via Direct Binding to Nucleoporins Nup62, Nup153, and RanBP2/Nup358." Journal of Biological Chemistry 287, no. 2 (November 21, 2011): 819–31. http://dx.doi.org/10.1074/jbc.m111.299099.

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Sharma, Manisha, Cara Jamieson, Michael Johnson, Mark P. Molloy, and Beric R. Henderson. "Specific Armadillo repeat sequences facilitate β-catenin nuclear transport in live cells via direct binding to nucleoporins Nup62, Nup153, and RanBP2/Nup358." Journal of Biological Chemistry 291, no. 9 (February 26, 2016): 4342. http://dx.doi.org/10.1074/jbc.a111.299099.

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Chen, Shane, Maria Lyanguzova, Ross Kaufhold, Karen M. Plevock Haase, Hangnoh Lee, Alexei Arnaoutov, and Mary Dasso. "Association of RanGAP to nuclear pore complex component, RanBP2/Nup358, is required for pupal development in Drosophila." Cell Reports 37, no. 13 (December 2021): 110151. http://dx.doi.org/10.1016/j.celrep.2021.110151.

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Gervais, C., L. Dano, N. Perrusson, C. Hélias, E. Jeandidier, A.-C. Galoisy, A. Ittel, R. Herbrecht, K. Bilger, and L. Mauvieux. "A translocation t(2;8)(q12;p11) fuses FGFR1 to a novel partner gene, RANBP2/NUP358, in a myeloproliferative/myelodysplastic neoplasm." Leukemia 27, no. 5 (October 8, 2012): 1186–88. http://dx.doi.org/10.1038/leu.2012.286.

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Sabri, Nafiseh, Peggy Roth, Nikos Xylourgidis, Fatemeh Sadeghifar, Jeremy Adler, and Christos Samakovlis. "Distinct functions of the Drosophila Nup153 and Nup214 FG domains in nuclear protein transport." Journal of Cell Biology 178, no. 4 (August 6, 2007): 557–65. http://dx.doi.org/10.1083/jcb.200612135.

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The phenylanine-glycine (FG)–rich regions of several nucleoporins both bind to nuclear transport receptors and collectively provide a diffusion barrier to the nuclear pores. However, the in vivo roles of FG nucleoporins in transport remain unclear. We have inactivated 30 putative nucleoporins in cultured Drosophila melanogaster S2 cells by RNA interference and analyzed the phenotypes on importin α/β−mediated import and CRM1-dependent protein export. The fly homologues of FG nucleoporins Nup358, Nup153, and Nup54 are selectively required for import. The FG repeats of Nup153 are necessary for its function in transport, whereas the remainder of the protein maintains pore integrity. Inactivation of the CRM1 cofactor RanBP3 decreased the nuclear accumulation of CRM1 and protein export. We report a surprisingly antagonistic relationship between RanBP3 and the Nup214 FG region in determining CRM1 localization and its function in protein export. Our data suggest that peripheral metazoan FG nucleoporins have distinct functions in nuclear protein transport events.

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Hofemeister, Helmut, and Peter O'Hare. "Nuclear Pore Composition and Gating in Herpes Simplex Virus-Infected Cells." Journal of Virology 82, no. 17 (June 18, 2008): 8392–99. http://dx.doi.org/10.1128/jvi.00951-08.

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ABSTRACT The mechanism by which herpes simplex virus (HSV) exits the nucleus remains a matter of controversy. The generally accepted route proposes that capsids exit via primary envelopment at the inner nuclear membrane and subsequent fusion of this primary particle with the outer nuclear membrane to gain capsid entry to the cytoplasm. However, recent observations indicate that HSV may induce gross morphological alterations of nuclear pores, resulting in the loss of normal pores and the appearance of dilated gaps in the nuclear membrane of up to several 100 nm. On this basis, it was proposed that a main route of capsid exit from the nucleus is directly through these altered pores. Here, we examine the biochemical composition of some of the major nuclear pore components in uninfected and HSV-infected cells. We show that total levels of major nucleoporins and their sedimentation patterns in density gradients remain largely unchanged up to 18 h after HSV infection. Some alteration in modification of one nucleoporin, Nup358/RanBP2, was observed during enrichment with anti-nucleoporin antibody and probing for O glycosylation. In addition, we examine functional gating within the nucleus in live cells, using microinjection of labeled dextran beads and a recombinant virus expressing GFP-VP16 to track the progress of infection. The nuclear permeability barrier for molecules bigger than 70 kDa remained intact throughout infection. Thus, in a functional assay in live cells, we find no evidence for gross perturbation to the gating of nuclear pores, although this might not exclude a small population of modified pores.

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Cordes, Volker C., Sonja Reidenbach, Hans-Richard Rackwitz, and Werner W. Franke. "Identification of Protein p270/Tpr as a Constitutive Component of the Nuclear Pore Complex–attached Intranuclear Filaments." Journal of Cell Biology 136, no. 3 (February 10, 1997): 515–29. http://dx.doi.org/10.1083/jcb.136.3.515.

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Using a monoclonal antibody, mAb 203-37, we have identified a polypeptide of Mr ∼270 kD (p270) as a general constituent of the intranuclear filaments attached to the nucleoplasmic annulus of the nuclear pore complex (NPC) in diverse kinds of vertebrate cells. Using cDNA cloning and immunobiochemistry, we show that human protein p270 has a predicted molecular mass of 267 kD and is essentially identical to the coiled-coil dominated protein Tpr reported by others to be located on the outer, i.e., cytoplasmic surface of NPCs (Byrd, D.A., D.J. Sweet, N. Pante, K.N. Konstantinov, T. Guan, A.C.S. Saphire, P.J. Mitchell, C.S. Cooper, U. Aebi, and L. Gerace. 1994. J. Cell Biol. 127: 1515–1526). To clarify this controversial localization, we have performed immunoelectron microscopy in diverse kinds of mammalian and amphibian cells with a series of antibodies raised against different epitopes of human and Xenopus laevis p270/Tpr. In these experiments, the protein has been consistently and exclusively detected in the NPC-attached intranuclear filaments, and p270/Tpr-containing filament bundles have been traced into the nuclear interior for up to 350 nm. No reaction has been noted at the cytoplasmic side of NPCs with any of the p270/Tpr antibodies, whereas control antibodies such as those against protein RanBP2/ Nup358 specifically decorate the cytoplasmic annulus of NPCs. Pore complexes of cytoplasmic annulate lamellae in various mammalian and amphibian cells are also devoid of immunodetectable protein p270/Tpr. We conclude that this coiled-coil protein is a general and ubiquitous component of the intranuclear NPC- attached filaments and discuss its possible functions.

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Oka, Masahiro, Munehiro Asally, Yoshinari Yasuda, Yutaka Ogawa, Taro Tachibana, and Yoshihiro Yoneda. "The Mobile FG Nucleoporin Nup98 Is a Cofactor for Crm1-dependent Protein Export." Molecular Biology of the Cell 21, no. 11 (June 2010): 1885–96. http://dx.doi.org/10.1091/mbc.e09-12-1041.

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Nup98 is a mobile nucleoporin that forms distinct dots in the nucleus, and, although a role for Nup98 in nuclear transport has been suggested, its precise function remains unclear. Here, we show that Nup98 plays an important role in Crm1-mediated nuclear protein export. Nuclear, but not cytoplasmic, dots of EGFP-tagged Nup98 disappeared rapidly after cell treatment with leptomycin B, a specific inhibitor of the nuclear export receptor, Crm1. Mutational analysis demonstrated that Nup98 physically and functionally interacts with Crm1 in a RanGTP-dependent manner through its N-terminal phenylalanine-glycine (FG) repeat region. Moreover, the activity of the Nup98-Crm1 complex was modulated by RanBP3, a known cofactor for Crm1-mediated nuclear export. Finally, cytoplasmic microinjection of anti-Nup98 inhibited the Crm1-dependent nuclear export of proteins, concomitant with the accumulation of anti-Nup98 in the nucleus. These results clearly demonstrate that Nup98 functions as a novel shuttling cofactor for Crm1-mediated nuclear export in conjunction with RanBP3.

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Haraguchi, T., T. Koujin, T. Hayakawa, T. Kaneda, C. Tsutsumi, N. Imamoto, C. Akazawa, J. Sukegawa, Y. Yoneda, and Y. Hiraoka. "Live fluorescence imaging reveals early recruitment of emerin, LBR, RanBP2, and Nup153 to reforming functional nuclear envelopes." Journal of Cell Science 113, no. 5 (March 1, 2000): 779–94. http://dx.doi.org/10.1242/jcs.113.5.779.

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We determined the times when the nuclear membrane, nuclear pore complex (NPC) components, and nuclear import function were recovered during telophase in living HeLa cells. Simultaneous observation of fluorescently-labeled NLS-bearing proteins, lamin B receptor (LBR)-GFP, and Hoechst33342-stained chromosomes revealed that nuclear membranes reassembled around chromosomes by 5 minutes after the onset of anaphase (early telophase) whereas nuclear import function was recovered later, at 8 minutes. GFP-tagged emerin also accumulated on chromosomes 5 minutes after the onset of anaphase. Interestingly, emerin and LBR initially accumulated at distinct, separate locations, but then became uniform 8 minutes after the onset of anaphase, concurrent with the recovery of nuclear import function. We further determined the timing of NPC assembly by immunofluorescence staining of cells fixed at precise times after the onset of anaphase. Taken together, these results showed that emerin, LBR, and several NPC components (RanBP2, Nup153, p62), but not Tpr, reconstitute around chromosomes very early in telophase prior to the recovery of nuclear import activity.

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Lévesque, Lyne, Yeou-Cherng Bor, Leah H. Matzat, Li Jin, Stephen Berberoglu, David Rekosh, Marie-Louise Hammarskjöld, and Bryce M. Paschal. "Mutations in Tap Uncouple RNA Export Activity from Translocation through the Nuclear Pore Complex." Molecular Biology of the Cell 17, no. 2 (February 2006): 931–43. http://dx.doi.org/10.1091/mbc.e04-07-0634.

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Interactions between transport receptors and phenylalanine-glycine (FG) repeats on nucleoporins drive the translocation of receptor-cargo complexes through nuclear pores. Tap, a transport receptor that mediates nuclear export of cellular mRNAs, contains a UBA-like and NTF2-like folds that can associate directly with FG repeats. In addition, two nuclear export sequences (NESs) within the NTF2-like region can also interact with nucleoporins. The Tap-RNA complex was shown to bind to three nucleoporins, Nup98, p62, and RanBP2, and these interactions were enhanced by Nxt1. Mutations in the Tap-UBA region abolished interactions with all three nucleoporins, whereas the effect of point mutations within the NTF2-like domain of Tap known to disrupt Nxt1 binding or nucleoporin binding were nucleoporin dependent. A mutation in any of these Tap domains was sufficient to reduce RNA export but was not sufficient to disrupt Tap interaction with the NPC in vivo or its nucleocytoplasmic shuttling. However, shuttling activity was reduced or abolished by combined mutations within the UBA and either the Nxt1-binding domain or NESs. These data suggest that Tap requires both the UBA- and NTF2-like domains to mediate the export of RNA cargo, but can move through the pores independently of these domains when free of RNA cargo.

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De Keersmaecker, Kim, Rafael Bernad, Cedric Folens, Nicole Mentens, Peter Marynen, Maarten Fornerod, and Jan Cools. "Oncogenic Properties of the T-ALL Associated EML1-ABL1 and NUP214-ABL1 Fusion Proteins." Blood 108, no. 11 (November 16, 2006): 1830. http://dx.doi.org/10.1182/blood.v108.11.1830.1830.

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Abstract BCR-ABL1 is frequently associated with CML and B-ALL, but is rarely found in T-ALL. We recently identified two variant ABL1 fusions in T-ALL: NUP214-ABL1, associated with episomal amplification of ABL1 in 6% of T-ALL cases, and EML1-ABL1, associated with the cryptic translocation t(9;14)(q34;q32) in 1 patient. Similar to BCR-ABL1, NUP214-ABL1 and EML1-ABL1 are constitutively activated tyrosine kinases that transform the Ba/F3 cell line to interleukin-3 (IL3) independent growth. In the case of NUP214-ABL1, however, the Ba/F3 cells need a significantly longer period to obtain the same level of proliferation compared to BCR-ABL1 and EML1-ABL1 transformed cells. In mouse bone marrow transplantation experiments, BCR-ABL1 induced CML with a latency of 3 weeks, while with EML1-ABL1 the mice developed disease after several months, and for NUP214-ABL1 no leukemia developed within 12 months after transplantation. These data suggest that EML1-ABL1 and NUP214-ABL1 are weaker oncogenes compared to BCR-ABL1. To gain further insights in these differences, we generated a number of deletion constructs of BCR-ABL1, EML1-ABL1 and NUP214-ABL1 and assayed the respective proteins for autophosphorylation and for their ability to transform Ba/F3 cells. For BCR-ABL1, we observed that the coiled-coil domain is not strictly required for kinase activity and transformation of Ba/F3 cells, as reported previously. In contrast, the coiled-coil domain of EML1 is sufficient and required to generate a constitutively activated EML1-ABL1 fusion protein. In the case of NUP214-ABL1, the coiled-coil domains are required, but not sufficient to generate an activated NUP214-ABL1 fusion in Ba/F3 cells, and also deletion of the N-terminal and C-terminal regions of NUP214 results in a loss of activity of NUP214-ABL1. Additional experiments confirmed that EML1-ABL1 is activated through homodimerization, while the exact mechanism of activation of NUP214-ABL1 remains unclear. In contrast to BCR-ABL1 and EML1-ABL1, NUP214-ABL1 seems to have a lower kinase activity and lacks detectable phosphorylation of the activation loop of the kinase domain. NUP214-ABL1 interacts with the nuclear pore proteins NUP62, NUP88 and RanBP2, is partially localized at the nuclear envelope, and phosphorylates RanBP2. In conclusion, we describe significant differences between BCR-ABL1, EML1-ABL1 and NUP214-ABL1. For BCR-ABL1, the coiled-coil domain is sufficient for kinase activation, however BCR-ABL1 can also be activated by coiled-coil independent mechanisms. These mechanisms explain the high kinase activity and strong transforming capacity of BCR-ABL1. For EML1-ABL1, the coiled-coil domain is the only domain that can activate the kinase, probably explaining its weaker transforming capacity in mouse bone marrow transplantation models when compared to BCR-ABL1. NUP214-ABL1 is a very weak oncogene, the coiled-coil domains of NUP214 need to cooperate with other domains to activate NUP214-ABL1 adequately in Ba/F3 cells. These results may explain why NUP214-ABL1 is always amplified in T-ALL patients, and why NUP214-ABL1 is associated with T-ALL and not with CML.

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Ogawa, Yuki, and Matthew N. Rasband. "Endogenously expressed Ranbp2 is not at the axon initial segment." Journal of Cell Science 134, no. 6 (March 11, 2021). http://dx.doi.org/10.1242/jcs.256180.

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ABSTRACT Ranbp2 (also known as Nup358) is a member of the nucleoporin family, which constitutes the nuclear pore complex. Ranbp2 localizes at the nuclear membrane and was recently reported at the axon initial segment (AIS). However, we show that the anti-Ranbp2 antibody used in previous studies is not specific for Ranbp2. We mapped the antibody binding site to the amino acid sequence KPLQG, which is present in both Ranbp2 and neurofascin (Nfasc), a well-known AIS protein. After silencing neurofascin expression in neurons, the AIS was not stained by the antibody. Surprisingly, an exogenously expressed N-terminal fragment of Ranbp2 localizes at the AIS. We show that this fragment interacts with stable microtubules. Finally, using CRISPR/Cas9 in primary cultured neurons, we inserted an HA-epitope tag at N-terminal, C-terminal or internal sites of the endogenously expressed Ranbp2. No matter the location of the HA-epitope, endogenous Ranbp2 was found at the nuclear membrane but not the AIS. These results show that endogenously expressed Ranbp2 is not found at AISs. This article has an associated First Person interview with the first author of the paper.

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He, Yujiao, Zhiguo Yang, Chen-si Zhao, Zhihui Xiao, Yu Gong, Yun-Yi Li, Yiqi Chen, et al. "T-cell receptor (TCR) signaling promotes the assembly of RanBP2/RanGAP1-SUMO1/Ubc9 nuclear pore subcomplex via PKC-θ-mediated phosphorylation of RanGAP1." eLife 10 (June 10, 2021). http://dx.doi.org/10.7554/elife.67123.

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The nuclear pore complex (NPC) is the sole and selective gateway for nuclear transport, and its dysfunction has been associated with many diseases. The metazoan NPC subcomplex RanBP2, which consists of RanBP2 (Nup358), RanGAP1-SUMO1, and Ubc9, regulates the assembly and function of the NPC. The roles of immune signaling in regulation of NPC remain poorly understood. Here, we show that in human and murine T cells, following T-cell receptor (TCR) stimulation, protein kinase C-θ (PKC-θ) directly phosphorylates RanGAP1 to facilitate RanBP2 subcomplex assembly and nuclear import and, thus, the nuclear translocation of AP-1 transcription factor. Mechanistically, TCR stimulation induces the translocation of activated PKC-θ to the NPC, where it interacts with and phosphorylates RanGAP1 on Ser504 and Ser506. RanGAP1 phosphorylation increases its binding affinity for Ubc9, thereby promoting sumoylation of RanGAP1 and, finally, assembly of the RanBP2 subcomplex. Our findings reveal an unexpected role of PKC-θ as a direct regulator of nuclear import and uncover a phosphorylation-dependent sumoylation of RanGAP1, delineating a novel link between TCR signaling and assembly of the RanBP2 NPC subcomplex.

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Desgraupes, Sophie, Lucie Etienne, and Nathalie J. Arhel. "RANBP2 Evolution and Human Disease." FEBS Letters, October 5, 2023. http://dx.doi.org/10.1002/1873-3468.14749.

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RANBP2/Nup358 (Ran Binding Protein 2) is a nucleoporin and a key component of the nuclear pore complex. Through its multiple functions (e.g. SUMOylation, regulation of nucleocytoplasmic transport) and subcellular localizations (e.g. at the nuclear envelope, kinetochores, annulate lamellae), it is involved in many cellular processes. RANBP2 dysregulation or mutation leads to the development of human pathologies, such as Acute Necrotizing Encephalopathy 1 (ANE1), cancer, neurodegenerative diseases and it is also involved in viral infections. The chromosomal region containing the RANBP2 gene is highly dynamic, with high structural variation and recombination events that led to the appearance of a gene family called RGPD (RANBP2 and GCC2 Protein Domains), with multiple gene loss/duplication events during ape evolution. Although RGPD homoplasy and maintenance during evolution suggest they might confer an advantage to their hosts, their functions are still unknown and understudied. In this review, we discuss the appearance and importance of RANBP2 in metazoans and its function‐related pathologies, caused by an alteration of its expression levels (through promotor activity, post‐transcriptional or post‐translational modifications), its localization or genetic mutations.

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Deursen, Jan M., Meelad Dawlaty, Karthik Jeganathan, and Malureanu Liviu. "RanBP2/Nup358 is required for Topoisomerase II/alpha‐mediated DNA decatenation, proper chromosome segregation and tumor suppression." FASEB Journal 21, no. 5 (April 2007). http://dx.doi.org/10.1096/fasebj.21.5.a210.

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Izumi, Rumiko, Kensuke Ikeda, Tetsuya Niihori, Naoki Suzuki, Matsuyuki Shirota, Ryo Funayama, Keiko Nakayama, et al. "Nuclear pore pathology underlying multisystem proteinopathy type 3‐related inclusion body myopathy." Annals of Clinical and Translational Neurology, December 29, 2023. http://dx.doi.org/10.1002/acn3.51977.

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AbstractObjectiveMultisystem proteinopathy type 3 (MSP3) is an inherited, pleiotropic degenerative disorder caused by a mutation in heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1), which can affect the muscle, bone, and/or nervous system. This study aimed to determine detailed histopathological features and transcriptomic profile of HNRNPA1‐mutated skeletal muscles to reveal the core pathomechanism of hereditary inclusion body myopathy (hIBM), a predominant phenotype of MSP3.MethodsHistopathological analyses and RNA sequencing of HNRNPA1‐mutated skeletal muscles harboring a c.940G > A (p.D314N) mutation (NM_031157) were performed, and the results were compared with those of HNRNPA1‐unlinked hIBM and control muscle tissues.ResultsRNA sequencing revealed aberrant alternative splicing events that predominantly occurred in myofibril components and mitochondrial respiratory complex. Enrichment analyses identified the nuclear pore complex (NPC) and nucleocytoplasmic transport as suppressed pathways. These two pathways were linked by the hub genes NUP50, NUP98, NUP153, NUP205, and RanBP2. In immunohistochemistry, these nucleoporin proteins (NUPs) were mislocalized to the cytoplasm and aggregated mostly with TAR DNA‐binding protein 43 kDa and, to a lesser extent, with hnRNPA1. Based on ultrastructural observation, irregularly shaped myonuclei with deep invaginations were frequently observed in atrophic fibers, consistent with the disorganization of NPCs. Additionally, regarding the expression profiles of overall NUPs, reduced expression of NUP98, NUP153, and RanBP2 was shared with HNRNPA1‐unlinked hIBMs.InterpretationThe shared subset of altered NUPs in amyotrophic lateral sclerosis (ALS), as demonstrated in prior research, HNRNPA1‐mutated, and HNRNPA1‐unlinked hIBM muscle tissues may provide evidence regarding the underlying common nuclear pore pathology of hIBM, ALS, and MSP.

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Kane, Melissa, Stephanie V. Rebensburg, Matthew A. Takata, Trinity M. Zang, Masahiro Yamashita, Mamuka Kvaratskhelia, and Paul D. Bieniasz. "Nuclear pore heterogeneity influences HIV-1 infection and the antiviral activity of MX2." eLife 7 (August 7, 2018). http://dx.doi.org/10.7554/elife.35738.

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HIV-1 accesses the nuclear DNA of interphase cells via a poorly defined process involving functional interactions between the capsid protein (CA) and nucleoporins (Nups). Here, we show that HIV-1 CA can bind multiple Nups, and that both natural and manipulated variation in Nup levels impacts HIV-1 infection in a manner that is strikingly dependent on cell-type, cell-cycle, and cyclophilin A (CypA). We also show that Nups mediate the function of the antiviral protein MX2, and that MX2 can variably inhibit non-viral NLS function. Remarkably, both enhancing and inhibiting effects of cyclophilin A and MX2 on various HIV-1 CA mutants could be induced or abolished by manipulating levels of the Nup93 subcomplex, the Nup62 subcomplex, NUP88, NUP214, RANBP2, or NUP153. Our findings suggest that several Nup-dependent ‘pathways’ are variably exploited by HIV-1 to target host DNA in a cell-type, cell-cycle, CypA and CA-sequence dependent manner, and are differentially inhibited by MX2.

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Ling, Yue-Huan, Hao Wang, Mei-Qing Han, Di Wang, Yi-Xiang Hu, Kun Zhou, and Yan Li. "Nucleoporin 85 interacts with influenza A virus PB1 and PB2 to promote its replication by facilitating nuclear import of ribonucleoprotein." Frontiers in Microbiology 13 (August 16, 2022). http://dx.doi.org/10.3389/fmicb.2022.895779.

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Transcription and replication of the influenza A virus (IAV) genome take place in the nucleus of infected cells, which rely on host factors to aid viral ribonucleoprotein (vRNP) to cross the nuclear pore complex (NPC) and complete the bidirectional nucleocytoplasmic trafficking. Here, we showed that nucleoporin 85 (NUP85), a component of NPC, interacted with RNP subunits polymerase basic 1 (PB1) and polymerase basic 2 (PB2) in an RNA-dependent manner during IAV infection. Knockdown of NUP85 delayed the nuclear import of vRNP, PB1 and PB2, inhibiting polymerase activity and ultimately suppressing viral replication. Further analysis revealed that NUP85 assisted the binding of PB1 to nuclear transport factor Ran-binding protein 5 (RanBP5) and the binding of PB2 to nuclear transport factor importin α1 and importin α7. We also found that NUP85 expression was downregulated upon IAV infection. Together, our study demonstrated that NUP85 positively regulated IAV infection by interacting with viral PB1 and PB2, which may provide new insight into the process of vRNP nuclear import and a novel target for effective antivirals.

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Journal articles on the topic 'RanBP2 (Nup358)'

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