bims-nucpor Biomed News
on Nuclear pore complex and nucleoporins in stress, aging and disease
Issue of 2023‒07‒23
six papers selected by
Sara Mingu, Johannes Gutenberg University
  1. Mechanisms of nuclear pore complex disassembly by the mitotic Polo-like kinase 1 (PLK-1) in C. elegans embryos.
  2. Super-resolution microscopy reveals focal organization of ER-associated Y-complexes in mitosis.
  3. KPNB1-mediated nuclear import in cancer.
  4. Nucleoporin Seh1 maintains Schwann cell homeostasis by regulating genome stability and necroptosis.
  5. A murine model of hnRNPH2-related neurodevelopmental disorder reveals a mechanism for genetic compensation by Hnrnph1.
  6. Bifunctional small molecules that induce nuclear localization and targeted transcriptional regulation.
  1. Sci Adv. 2023 Jul 21. 9(29): eadf7826
    Mechanisms of nuclear pore complex disassembly by the mitotic Polo-like kinase 1 (PLK-1) in C. elegans embryos.
    Sylvia Nkombo Nkoula, Griselda Velez-Aguilera, Batool Ossareh-Nazari, Lucie Van Hove, Cristina Ayuso, Véronique Legros, Guillaume Chevreux, Laura Thomas, Géraldine Seydoux, Peter Askjaer, Lionel Pintard.
      The nuclear envelope, which protects and organizes the genome, is dismantled during mitosis. In the Caenorhabditis elegans zygote, nuclear envelope breakdown (NEBD) of the parental pronuclei is spatially and temporally regulated during mitosis to promote the unification of the maternal and paternal genomes. Nuclear pore complex (NPC) disassembly is a decisive step of NEBD, essential for nuclear permeabilization. By combining live imaging, biochemistry, and phosphoproteomics, we show that NPC disassembly is a stepwise process that involves Polo-like kinase 1 (PLK-1)-dependent and -independent steps. PLK-1 targets multiple NPC subcomplexes, including the cytoplasmic filaments, central channel, and inner ring. PLK-1 is recruited to and phosphorylates intrinsically disordered regions (IDRs) of several multivalent linker nucleoporins. Notably, although the phosphosites are not conserved between human and C. elegans nucleoporins, they are located in IDRs in both species. Our results suggest that targeting IDRs of multivalent linker nucleoporins is an evolutionarily conserved driver of NPC disassembly during mitosis.
    DOI:  https://doi.org/10.1126/sciadv.adf7826
  2. EMBO Rep. 2023 Jul 20. e56766
    Super-resolution microscopy reveals focal organization of ER-associated Y-complexes in mitosis.
    Rojapriyadharshini Gandhimathi, Dorothea Pinotsi, Mario Köhler, Jörg Mansfeld, Caroline Ashiono, Tatjana Kleele, Sumit Pawar, Ulrike Kutay.
      During mitotic entry of vertebrate cells, nuclear pore complexes (NPCs) are rapidly disintegrated. NPC disassembly is initiated by hyperphosphorylation of linker nucleoporins (Nups), which leads to the dissociation of FG repeat Nups and relaxation of the nuclear permeability barrier. However, less is known about disintegration of the huge nuclear and cytoplasmic rings, which are formed by annular assemblies of Y-complexes that are dissociated from NPCs as intact units. Surprisingly, we observe that Y-complex Nups display slower dissociation kinetics compared with other Nups during in vitro NPC disassembly, indicating a mechanistic difference in the disintegration of Y-based rings. Intriguingly, biochemical experiments reveal that a fraction of Y-complexes remains associated with mitotic ER membranes, supporting recent microscopic observations. Visualization of mitotic Y-complexes by super-resolution microscopy demonstrates that they form two classes of higher order assemblies: large clusters at kinetochores and small, focal ER-associated assemblies. These, however, lack features qualifying them as persisting ring-shaped subassemblies previously proposed to serve as structural templates for NPC reassembly during mitotic exit, which helps to refine current models of nuclear reassembly.
    Keywords:  NPC disassembly; Y-complex; mitosis; nuclear pore complex; nucleoporin
    DOI:  https://doi.org/10.15252/embr.202356766
  3. Eur J Pharmacol. 2023 Jul 18. pii: S0014-2999(23)00437-5. [Epub ahead of print] 175925
    KPNB1-mediated nuclear import in cancer.
    Qiwen Shi, Mengxia Lin, Xiang Cheng, Ziyuan Zhang, Shufen Deng, Ke Lang, Zhikun Yang, Xuanrong Sun.
      Dysregulation of nucleocytoplasmic shuttling impairs cellular homeostasis and promotes cancer development. KPNB1 is a member of karyopherin β family, mediating the transportation of proteins from the cytoplasm to the nucleus. In a variety of cancers, the expression of KPNB1 is upregulated to facilitate tumor growth and progression. Both downregulation of KPNB1 level and inhibition of KPNB1 activity prevent the entry of cancer-related transcription factors into the nucleus, subsequently suppressing the proliferation and metastasis of cancer cells. Currently, five KPNB1 inhibitors have been reported and exhibited good efficacy against cancer. This paper provides an overview of the role and mechanism of KPNB1 in different cancers and KPNB1-targeted anticancer compounds which hold promise for the future.
    Keywords:  Apoptosis; Cancer; Cell cycle; KPNB1; Nucleocytoplasmic transport
    DOI:  https://doi.org/10.1016/j.ejphar.2023.175925
  4. Cell Rep. 2023 Jul 14. pii: S2211-1247(23)00813-6. [Epub ahead of print]42(7): 112802
    Nucleoporin Seh1 maintains Schwann cell homeostasis by regulating genome stability and necroptosis.
    Mei Wu, Man Li, Wei Liu, Minbiao Yan, Li Li, Weichao Ding, Ximing Nian, Wenxiu Dai, Di Sun, Yanqin Zhu, Qiuying Huang, Xiaoyun Lu, Zhiyu Cai, Fan Hong, Xuewen Li, Ling Zhang, Zhixiong Liu, Wei Mo, Xueqin Zhang, Liang Zhang.
      Schwann cells play critical roles in peripheral neuropathies; however, the regulatory mechanisms of their homeostasis remain largely unknown. Here, we show that nucleoporin Seh1, a component of nuclear pore complex, is important for Schwann cell homeostasis. Expression of Seh1 decreases as mice age. Loss of Seh1 leads to activated immune responses and cell necroptosis. Mice with depletion of Seh1 in Schwann cell lineage develop progressive reduction of Schwann cells in sciatic nerves, predominantly non-myelinating Schwann cells, followed by neural fiber degeneration and malfunction of the sensory and motor system. Mechanistically, Seh1 safeguards genome stability by mediating the interaction between SETDB1 and KAP1. The disrupted interaction after ablation of Seh1 derepresses endogenous retroviruses, which triggers ZBP1-dependent necroptosis in Schwann cells. Collectively, our results demonstrate that Seh1 is required for Schwann cell homeostasis by maintaining genome integrity and suggest that decrease of nucleoporins may participate in the pathogenesis of periphery neuropathies.
    Keywords:  CP: Neuroscience; Remak bundle; myelin; non-myelinating Schwann cell; nucleoporin; peripheral neuropathy
    DOI:  https://doi.org/10.1016/j.celrep.2023.112802
  5. J Clin Invest. 2023 07 17. pii: e160309. [Epub ahead of print]133(14):
    A murine model of hnRNPH2-related neurodevelopmental disorder reveals a mechanism for genetic compensation by Hnrnph1.
    Ane Korff, Xiaojing Yang, Kevin O'Donovan, Abner Gonzalez, Brett Jw Teubner, Haruko Nakamura, James Messing, Fen Yang, Alexandre F Carisey, Yong-Dong Wang, Tushar Patni, Heather Sheppard, Stanislav S Zakharenko, Yuh Min Chook, J Paul Taylor, Hong Joo Kim.
      Mutations in HNRNPH2 cause an X-linked neurodevelopmental disorder with features that include developmental delay, motor function deficits, and seizures. More than 90% of patients with hnRNPH2 have a missense mutation within or adjacent to the nuclear localization signal (NLS) of hnRNPH2. Here, we report that hnRNPH2 NLS mutations caused reduced interaction with the nuclear transport receptor Kapβ2 and resulted in modest cytoplasmic accumulation of hnRNPH2. We generated 2 knockin mouse models with human-equivalent mutations in Hnrnph2 as well as Hnrnph2-KO mice. Knockin mice recapitulated clinical features of the human disorder, including reduced survival in male mice, impaired motor and cognitive functions, and increased susceptibility to audiogenic seizures. In contrast, 2 independent lines of Hnrnph2-KO mice showed no detectable phenotypes. Notably, KO mice had upregulated expression of Hnrnph1, a paralog of Hnrnph2, whereas knockin mice failed to upregulate Hnrnph1. Thus, genetic compensation by Hnrnph1 may counteract the loss of hnRNPH2. These findings suggest that HNRNPH2-related disorder may be driven by a toxic gain of function or a complex loss of HNRNPH2 function with impaired compensation by HNRNPH1. The knockin mice described here are an important resource for preclinical studies to assess the therapeutic benefit of gene replacement or knockdown of mutant hnRNPH2.
    Keywords:  Neurological disorders; Neuroscience
    DOI:  https://doi.org/10.1172/JCI160309
  6. bioRxiv. 2023 Jul 07. pii: 2023.07.07.548101. [Epub ahead of print]
    Bifunctional small molecules that induce nuclear localization and targeted transcriptional regulation.
    William J Gibson, Ananthan Sadagopan, Veronika M Shoba, Amit Choudhary, Matthew Meyerson, Stuart L Schreiber.
      The aberrant localization of proteins in cells is a key factor in the development of various diseases, including cancer and neurodegenerative disease. To better understand and potentially manipulate protein localization for therapeutic purposes, we engineered bifunctional compounds that bind to proteins in separate cellular compartments. We show these compounds induce nuclear import of cytosolic cargoes, using nuclear-localized BRD4 as a "carrier" for co-import and nuclear trapping of cytosolic proteins. We use this system to calculate kinetic constants for passive diffusion across the nuclear pore and demonstrate single-cell heterogeneity in response to these bifunctional molecules, with cells requiring high carrier to cargo expression for complete import. We also observe incorporation of cargoes into BRD4-containing condensates. Proteins shown to be substrates for nuclear transport include oncogenic mutant nucleophosmin (NPM1c) and mutant PI3K catalytic subunit alpha (PIK3CA E545K ), suggesting potential applications to cancer treatment. In addition, we demonstrate that chemical-induced localization of BRD4 to cytosolic-localized DNA-binding proteins, namely, IRF1 with a nuclear export signal, induces target gene expression. These results suggest that induced localization of proteins with bifunctional molecules enables the rewiring of cell circuitry with significant implications for disease therapy.
    DOI:  https://doi.org/10.1101/2023.07.07.548101
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