bims-nucpor Biomed News
on Nuclear pore complex and nucleoporins in stress, aging and disease
Issue of 2023–04–23
six papers selected by
Sara Mingu, Johannes Gutenberg University
  1. Improving the Hole Picture: Towards a Consensus on the Mechanism of Nuclear Transport.
  2. Dynamic molecular mechanism of the nuclear pore complex permeability barrier.
  3. Phase separation of nuclear pore complex facilitates selective nuclear transport to regulate plant defense against pathogen and pest invasion.
  4. Influenza virus mRNAs encode determinants for nuclear export via the cellular TREX-2 complex.
  5. HOS1 promotes plant tolerance to low-energy stress via the SnRK1 protein kinase.
  6. Acetylation regulates the nucleocytoplasmic distribution and oncogenic function of karyopherin alpha 2 in lung adenocarcinoma.
  1. ArXiv. 2023 Apr 06. pii: arXiv:2304.03230v1. [Epub ahead of print]
    Improving the Hole Picture: Towards a Consensus on the Mechanism of Nuclear Transport.
    David Cowburn, Michael Rout.
      Nuclear pore complexes (NPCs) mediate the exchange of materials between the nucleoplasm and cytoplasm, playing a key role in the separation of nucleic acids and proteins into their required compartments. The static structure of the NPC is relatively well defined by recent cryo EM and other studies. The functional roles of dynamic components in the pore of the NPC, phenylalanyl-glycyl (FG) repeat rich nucleoporins, is less clear because of our limited understanding of highly dynamic protein systems. These proteins form a restrained concentrate which interacts with and concentrates nuclear transport factors (NTRs) to provide facilitated nucleocytoplasmic transport of cargoes. Very rapid exchange among FG repeats and NTRs supports extremely fast facilitated transport, close to the rate of macromolecular diffusion in cytoplasm, while complexes without specific interactions are entropically excluded, though details on several aspects of the transport mechanism and FG repeat behaviors remain to be resolved. However, as discussed here, new technical approaches combined with more advanced modeling methods will likely provide an improved dynamic description of NPC transport, potentially at the atomic level in the near future. Such advances are likely to be of major benefit in comprehending the roles the malfunctioning NPC plays in cancer, aging, viral diseases, and neurodegeneration.
  2. bioRxiv. 2023 Apr 14. pii: 2023.03.31.535055. [Epub ahead of print]
    Dynamic molecular mechanism of the nuclear pore complex permeability barrier.
    Toshiya Kozai, Javier Fernandez-Martinez, Trevor van Eeuwen, Paola Gallardo, Larisa E Kapinos, Adam Mazur, Wenzhu Zhang, Jeremy Tempkin, Radhakrishnan Panatala, Maria Delgado-Izquierdo, Barak Raveh, Andrej Sali, Brian T Chait, Liesbeth M Veenhoff, Michael P Rout, Roderick Y H Lim.
      Nuclear pore complexes (NPCs) mediate nucleocytoplasmic transport of specific macromolecules while impeding the exchange of unsolicited material. However, key aspects of this gating mechanism remain controversial. To address this issue, we determined the nanoscopic behavior of the permeability barrier directly within yeast S. cerevisiae NPCs at transport-relevant timescales. We show that the large intrinsically disordered domains of phenylalanine-glycine repeat nucleoporins (FG Nups) exhibit highly dynamic fluctuations to create transient voids in the permeability barrier that continuously shape-shift and reseal, resembling a radial polymer brush. Together with cargo-carrying transport factors the FG domains form a feature called the central plug, which is also highly dynamic. Remarkably, NPC mutants with longer FG domains show interweaving meshwork-like behavior that attenuates nucleocytoplasmic transport in vivo. Importantly, the bona fide nanoscale NPC behaviors and morphologies are not recapitulated by in vitro FG domain hydrogels. NPCs also exclude self-assembling FG domain condensates in vivo, thereby indicating that the permeability barrier is not generated by a self-assembling phase condensate, but rather is largely a polymer brush, organized by the NPC scaffold, whose dynamic gating selectivity is strongly enhanced by the presence of transport factors.
    DOI:  https://doi.org/10.1101/2023.03.31.535055
  3. Mol Plant. 2023 Apr 18. pii: S1674-2052(23)00106-5. [Epub ahead of print]
    Phase separation of nuclear pore complex facilitates selective nuclear transport to regulate plant defense against pathogen and pest invasion.
    Jiaojiao Wang, Gaofeng Pei, Yupei Wang, Dewei Wu, Xiaokang Liu, Gaoming Li, Jianfang He, Xiaolin Zhang, Xiaoyi Shan, Pilong Li, Daoxin Xie.
      Nuclear pore complex (NPC), the sole exchange channel between nucleus and cytoplasm, is composed of several subcomplexes, among which, the central barrier determines the permeability/selectivity of NPC to dominate the nucleocytoplasmic trafficking essential for many important signaling events in yeast and mammals. How plant NPC central barrier controls selective transport is a crucial question remaining to be elucidated. Here, we uncovered that phase separation of the central barrier is critical for the permeability and selectivity of plant NPC to regulate various biotic stresses. Phenotypic assay of nup62 mutants and complementary lines showed that NUP62 positively regulates plant defense to Botrytis cinerea, one of the world's most disastrous plant pathogens. Furthermore, both in vivo imaging and in vitro biochemical evidence revealed that plant NPC central barrier undergoes phase separation to regulate selective nucleocytoplasmic transport of immune regulators, as exemplified by MPK3 essential for plant resistance to Botrytis cinerea. Moreover, genetic analysis demonstrated that NPC phase separation plays an important role in plant defense against fungal and bacterial infection as well as insect attack. These findings reveal that phase separation of the NPC central barrier serves as an important mechanism to mediate nucleocytoplasmic transport of immune regulators and activate plant defense against a broad range of biotic stresses.
    Keywords:  MPK3; Nuclear pore complex; phase separation; plant defense
    DOI:  https://doi.org/10.1016/j.molp.2023.04.008
  4. Nat Commun. 2023 Apr 21. 14(1): 2304
    Influenza virus mRNAs encode determinants for nuclear export via the cellular TREX-2 complex.
    Prasanna Bhat, Vasilisa Aksenova, Matthew Gazzara, Emily A Rex, Sadaf Aslam, Christina Haddad, Shengyan Gao, Matthew Esparza, Tolga Cagatay, Kimberly Batten, Sara S El Zahed, Alexei Arnaoutov, Hualin Zhong, Jerry W Shay, Blanton S Tolbert, Mary Dasso, Kristen W Lynch, Adolfo García-Sastre, Beatriz M A Fontoura.
      Nuclear export of influenza A virus (IAV) mRNAs occurs through the nuclear pore complex (NPC). Using the Auxin-Induced Degron (AID) system to rapidly degrade proteins, we show that among the nucleoporins localized at the nucleoplasmic side of the NPC, TPR is the key nucleoporin required for nuclear export of influenza virus mRNAs. TPR recruits the TRanscription and EXport complex (TREX)-2 to the NPC for exporting a subset of cellular mRNAs. By degrading components of the TREX-2 complex (GANP, Germinal-center Associated Nuclear Protein; PCID2, PCI domain containing 2), we show that influenza mRNAs require the TREX-2 complex for nuclear export and replication. Furthermore, we found that cellular mRNAs whose export is dependent on GANP have a small number of exons, a high mean exon length, long 3' UTR, and low GC content. Some of these features are shared by influenza virus mRNAs. Additionally, we identified a 45 nucleotide RNA signal from influenza virus HA mRNA that is sufficient to mediate GANP-dependent mRNA export. Thus, we report a role for the TREX-2 complex in nuclear export of influenza mRNAs and identified RNA determinants associated with the TREX-2-dependent mRNA export.
    DOI:  https://doi.org/10.1038/s41467-023-37911-0
  5. Plant J. 2023 Apr 19.
    HOS1 promotes plant tolerance to low-energy stress via the SnRK1 protein kinase.
    Leonor Margalha, Alexandre Elias, Borja Belda-Palazón, Bruno Peixoto, Ana Confraria, Elena Baena-González.
      Plants need to integrate internal and environmental signals to mount adequate stress responses. The NUCLEAR PORE COMPLEX (NPC) component HIGH EXPRESSION OF OSMOTICALLY RESPONSIVE GENES 1 (HOS1) is emerging as such an integrator, affecting responses to cold, heat, light and salinity. Stress conditions often converge in a low-energy signal that activates SUCROSE NON-FERMENTING 1-RELATED KINASE 1 (SnRK1) to promote stress tolerance and survival. Here, we explored the role of HOS1 in the SnRK1-dependent response to low-energy stress in Arabidopsis thaliana, using darkness as a treatment and a combination of genetic, biochemical, and phenotypic assays. We show that the induction of starvation genes and plant tolerance to prolonged darkness are defective in the hos1 mutant. HOS1 interacts physically with the SnRK1α1 catalytic subunit in yeast-two-hybrid and in planta, and the nuclear accumulation of SnRK1α1 is reduced in the hos1 mutant. Likewise, another NPC mutant, nup160, exhibits lower activation of starvation genes and decreased tolerance to prolonged darkness. Importantly, defects in low-energy responses in the hos1 background are rescued by fusing SnRK1α1 to a potent nuclear localization signal, or by sugar supplementation during the dark treatment. Altogether, this work demonstrates the importance of HOS1 for the nuclear accumulation of SnRK1α1, which is key for plant tolerance to low-energy conditions.
    Keywords:  Arabidopsis thaliana; HOS1; NUP160; SnRK1; low-energy stress; nuclear pore complex
    DOI:  https://doi.org/10.1111/tpj.16250
  6. Biochem Biophys Res Commun. 2023 Apr 07. pii: S0006-291X(23)00415-1. [Epub ahead of print]659 96-104
    Acetylation regulates the nucleocytoplasmic distribution and oncogenic function of karyopherin alpha 2 in lung adenocarcinoma.
    Hsiang-Pu Feng, Yu-Chin Liu, Chih-Liang Wang, Wei-Chao Liao, Jau-Song Yu, Chia-Jung Yu.
      Karyopherin subunit alpha 2 (KPNA2, importin α1) is a nucleoplasmic protein responsible for the nuclear import of proteins with classical nuclear localization signals. Aberrant nuclear accumulation of KPNA2 has been observed in numerous cancer tissues. AMP-activated protein kinase (AMPK) is involved in the phosphorylation and acetylation of KPNA2 in enterocytes. However, the impact of these post-translational modifications on modulating the nucleocytoplasmic distribution of KPNA2 and its oncogenic role remain unclear. Unlike nuclear accumulation of wild-type KPNA2, which promoted lung cancer cell migration, KPNA2 Lys22 acetylation-mimicking mutations (K22Q and K22Q/S105A) prevented nuclear localization of KPNA2 and reduced the cell migration ability. Cytosolic KPNA2 K22Q interacted with and restricted the nuclear entry of E2F transcription factor 1 (E2F1), an oncogenic cargo protein of KPNA2, in lung cancer cells. Intriguingly, the AMPK activator EX229 promoted the nuclear export of KPNA2 S105A. However, the CBP/p300 inhibitor CCS-1477 abolished this phenomenon, suggesting that CBP/p300-mediated acetylation of KPNA2 promoted KPNA2 nuclear export in lung cancer cells. Collectively, our findings suggest that the CBP/p300 positively regulates KPNA2 acetylation, which enhances its cytosolic localization and suppresses its oncogenic activity in lung cancer.
    Keywords:  Acetylation; Importin; KPNA2; Lung cancer; Nucleocytoplasmic transport
    DOI:  https://doi.org/10.1016/j.bbrc.2023.04.014
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